2-methyl-6-fluoro compounds of the pregnane series



United States Patent i 2,989,523 2-METHYL-6-FLUORO COMPOUNDS 0F THEPREGNANE SERIES Philip F. Beal III, John "A. Hogg, and Robert W.Jackson, Kalamazoo, Mich., assignors to The Upjohn Coinpany, Kalamazoo,Mich., a corporation of Michigan No Drawing. Filed June 9, 1958, Ser.No. 740,543

3 Claims. (Cl. zoo-239.55

This invention relates to novel 2-methyl-6a-fluoroandZ-methyl-Gfl-fluoro compounds of the pregnane series. It relates moreparticularly to the 606 and 6 8 epimeric forms of (A) 2-methy1-6-fluoroll-oxygenated-l 7a,2l -dihydroxy- 1,4-pregnadiene-3,ZO-diones and the2l-acylates thereof, for example, 2-methyl-6-fluoro-l 1 18,17a,2l-trihydroxy- 1,4- pregnadiene-3,20-diones and2-methyl-6-fiuorm17a,21-dihydroxy-l,4-pregnadiene-3,11,20-triones, andthe 2l-acylates thereof; (B)2a-methyl-6-fiuoro-9a-halo-1l-oxygenated-l7ot,21-dihydroxy-4-pregnene-3,ZO-dionesand the 21- 21-difluoro-1l-oxygenated-17ot-hydroxy-4-pregnene 3,2.0-,

diones and the corresponding l-dehydro-Z-methyl compounds, for example,ZwmethyI 6,2l-difluoro-l 1,8,17a-dihydroxy-4-pregnene-3,ZO-diones,2a-methyl-6,21-difluoro- 17a-hydroxy-4-pregnene-3,l1,20-triones,2-methyl-6,21-difluoro 1lfi,l7a-dihydroxy-1,4-pregnadiene-3,20 diones,and 2-methyl-6,2l-difluoro-17ot-hydroxy-l,4 pregnadiene- 3,11,ZO-triones; (F)2amethyl-6-fluoro-9whalo-ll-oxygenated-l7a-hydroxy-4-pregnene-3,ZO-dionesand the corresponding l-dehydro-Z-methyl compounds, for example,2ot-methyl-6-fluoro 9a-halo llfi,l7ot-dihydroxy-4-pregnene 3,20-diones,2a-methyl-6-fiuoro-9a-halo l7u-hydroxy-4-pregnene-3,ll,20-trior1es,2-methyl-6-fluoro 9ahalo-l1,8,17a-dihydroxy-l,4-pregnadiene-3,20-diones, and2-methyl-6-fluoro-9ahalo-l7ot-hydroxy-l,4 pregnadiene- 3,11,20-triones;(G)2ot-methyl-6,21-difluoro-9whalolloxygenated-17a-hydr0xy-4-pregnene-3,20-dionesand the corresponding l-dehydro-Z-methyl compounds, for exampleZa-methyI 6,21-difl11OTO-9whal0-llfi,17adihydroxy-4-pregnene-3,ZO-diones, 2a-methyl-6,2l-difluoro-9ahalo- 17u-hydroxy-4-pregnene-3J 1,20-triones, 2-rnethyl-6,-2l-difluoro-9a-halo-1118,170: dihydroxy-1,4-pregnadiene- 3,20-diones,and 2-methyl-6,2l-difluoro-9ahalo-l7othydroxy'lA-pregnadiene-Ll1,2.0-triones; novel steroid inter mediatesused in the preparation thereof and processes for the productionthereof.

This application is a continuation-in-part of copending applicationSerial No. 699,508, filed November 29, 1957 now Patent No. 2,838,502issued June 10, 1958.

The novel compounds of this invention, listed above under and P088685the valuable anti-rheumatoid arthritic, anti-inflammatory andglucocorticoid activity of the parent G-fiuoro compounds(2amethyl-6-fluorohydrocortisone and the 21- acylates thereof, and2ot-methyl-6-fluorocortisone and the 2l-acylates thereof). They possessa combination of 2,989,523 Patented June 20, 1961 high anti-inflammatoryand glucocorticoid activities with favorable mineralocorticoidproperties. The compounds are useful in the treatment of inflammatoryconditions of the skin, eyes and ears of humans andyaluable domesticanimals, contact dermatitis and other allergenic reactions. Thecompounds can be administered'in conventional dosage forms such. aspills, tablets and capsules for oral use or in conventionalliquid formsas are used with natural and synthetic cortical steroid hormones forparenteral use. For topical use they can be administered in the form ofointments, creams, lotion, and the like with or without coactingantibiotics, germicides and the like.

Starting materials for the processes of this invention, Zamlethyl-Ga-tlluoro-l 1p, 17a,2l-trihydroxy-4-pregnene 3,- ZO-dione,2a-niethyl-6a-fluoro 17a,2l-dihydroxy-4-pregnene-3,11,20-trione,2a-methyl-6flfluorol1fl,17ot,21 trihydroxy-4-pregnene-3,ZO-dione,2a-methyl-6B-fluor0-17a; 21-dihydroxy-4-pregnene-3,11,20-trione, and thel7-acylates thereof, represented by the following formula:

CHZOR OH X CHa" wherein X is selected from the group consisting of thecarbonyl radical O='O) and the hydroxymethylene radical CHOH), and R ishydrogen. or the acyl radical of an organic carbox'ylic acid,,preferably a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive, are disclosed in our copending applicationSerial No. 699,508, filed November 29, 1957 and disclosed in Preparation1 below.

In this application the wavy line (E) appearing at the 6-position is ageneric expression including the alpha (:1) and bet (,6) configmration.

GROUP A The novel 6a-fluoroand 6B-fluoro steroid compounds of Group (A),of the present invention 2-methyl-6-fluoro- 11oxygenated-1711,21-dihydroXy-l,4-pregnadiene-3,2O-di ones and the21-acylates thereof, for example 2-methyl-6- fllllOl'O-l 1B,17:,21-trihydroxy-l,4-pregnadiene-3,20-diones, 2-1rnethyl-6 fluorol7a,2ldihydroxy-l ,4-pregnadiene- 3,'l 1, 20-triones, and the Zlacylatesthereof, are represented by the following formula:

CHrOR 7 r1 wherein X and R have the meanings previously given.

The novel compounds of Group (A) and some of the processes of thepresent invention are illustratively represented by the followingreaction scheme:

CH: CH:

lCHflOR (IHEHOH OH: cm

i j i Q CH1" OH E i F F III IV i I l ICHzOAC CH: 6

wherein X and R have the meanings previously given, and wherein Ac isthe acyl radical of an organic carboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive.

According to the process of the present invention for the production of2-methyl-6-fiuoro-l 1-oxygenated-17a,21-dihydroxy-l,4-pregnadiene-3,20-dione and the 21-acylates thereof,represented by Formulae IV and V, compounds of the type represented byFormula III are dehydrogenated at the 1-position. The l-dehydrogenationof the selected6-fluoro-1l-oxygenated-17a,2l-dihydroxy-4-pregnene-3,20-dione, or the21-acylates thereof, represented by Formula HI, can be carried outeither by fermentative or chemical dehydrogenation.

Fermentative dehydrogenation comprises the use of microorganisms such asSeptomyxa, Corynebacterium, Fusanum, and the like, under fermentationconditions well known in the art (e.g., US. 2,602,769) and furthermoreillustrated by Examples 1A through 4A, herein. Where Septomyxa is usedto elfect the dehydrogenation it is found to be advantageous to use withthe substrate and medium a steroid promoter, such as progesterone,3-ketobisnor-4-cholen-22-al, 3-ketobisnorcholenic acid, 1118,21-dihydroxy-1,4,l7(20)-pregnatrien 3 one, and the like. The free alcoholsare usually employed as starting material for the fermentativedehydrogenation process. However, the selected Zea-methyl6-fluoro-l1-oxygenated-17a, 21-dihydroxyA-pregnene,ZO-dione 2l-acylatesof Formula HI can be used such as the 2l-acetate, 2l-propionate,ZI-butyrate, zl-isobutyrate, ZI-hemisuccinate, and the like. In thesecases the 2l-ester group is generally saponified during the fermentationprocess giving the corresponding2-methyl-6-fiuoro-l1-oxygenated-l7a,2l-dihydroxy-l,4-pregnadiene-3,20-dionerepresented by Formula IV. The ZI-free alcohol thus produced can bereacylated, if desired, by known 2l-acylation methods.

Chemical dehydrogenation can be carried out with selenium dioxideaccording to procedures well known in the art [Meystre et al., Helv.Chem. Acta, 39, 734 (1956)]. The 2l-acylates of Formula III aregenerally preferred as starting material in the chemical dehydrogenationreac- 4 tion giving the corresponding2a-methyl-6-fluoro-1l-oxygenated-17a,21-dihydroxy-1,4-pregnadiene-3,ZO-dione21- acylate represented by Formula V. The 2l-acylate thus obtained canbe saponified, if desired, by methods known in the art to give the2l-free alcohol of the corresponding 2l-acylate.

The 2-methyl-6-fluoro-11-oxygenated-17a,2l-dihydroxy-1,4-pregnadiene-3,ZO-diones, represented by Formula IV, can be convertedto the corresponding 2lacylates of Formula V by reaction with theselected acylating agent. This reaction can be performed under theesterification conditions known in the art, e.g., by the reaction of IVwith the selected acid halide or acid chloride or acid bromide or theanhydride of an organic carboxylic acid, or by reaction with theselected acid, in the presence of an esterification catalyst, forexample, p-toluenesulfonyl chloride, trifluoroacetic anhydride,p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and thelike, or with an ester under ester exchange reaction conditions.Reaction conditions which are apt to affect the labile ll-hydroxy groupor 6-halo group should be avoided. Compounds thus-produced include thecompounds represented by Formula V wherein Ac is the acyl radical of ahydrocarbon carboxylic acid containing from one to twelve carbon atoms,inclusive, for example, a saturated straight-chain aliphatic acid, e.g.,formic, acetic, propionic, butyric, valeric, hexanoic, lauric, asaturated branched-chain aliphatic acid, e.g., trimethylacetic,isobutyric, isovaleric, tertiary butylacetic, a cycloaliphatic saturatedacid, e.g., flcyclopentylpropionic, cyclohexane-carboxylic,cyclohexylacetic, an alkaryl acid, e.g., benzoic, phenylacetic,fi-phenylpropionic, o-, m-, and p-toluic, a saturated dibasic acid(which can be converted into water-soluble, e.g., sodium, salts), e.g.,succinic, adipic; a monobasic unsaturated acid, e.g., acrylic, crotonic,undecylenic, propiolic, undecolic, cinnamic; dibasic unsaturated acids(which can be converted into water-soluble, e.g., sodium, salts), e.g.,maleic and citraconic, and the like.

The 2-methyl-6-fluoro-11-oxygenated-17a,2l-dihydroxy- 1,4-pregnadiene3,20 dione 21-acylates of Formula V, thus-produced, can be hydrolyzed tothe corresponding 2]- hydroxy compounds of Formula IV in accordance withknown methods for hydrolyzing Compound F 2l-esters to the free- CompoundF alcohol. A preferred procedure is to employ at least a molarequivalent of an alkali metal bicarbonate in a substantially oxygen-freesolution of a mixture of a lower alkanol and water. The hydrolysisreaction is carried out at a temperature between ten and thirty degreescentigrade while protecting the mixture from atmospheric oxygen. Afterthe hydrolysis is complete, the reaction mixture is neutralized with anacid, e.g., acetic acid, and the hydrolyzed product recovered from thereaction mixture by evaporation and crystallization, extraction withmethylene chloride or the like.

The foregoing compounds III, IV and V are all characterized by thepresence of a 6-fiuoro substituent. It should be noted that theconfiguration of the fluorine at the 6-position can be either 60: or 65.Thus when 211- methyl 6fl-fluoro-l l-oxygenated'l7e,2l-dihydroxy-4-pregnene-3-20-dione or the 21-acylate thereof is usedas the starting steroid (III) and following the procedures hereinbeforedescribed and as exemplified below, while maintaining near neutralreaction conditions, there is produced as the final product thecorresponding 6fi-epimer. Where the GB-epimer or mixtures predominatingtherein is employed as the starting material, any subsequent reactionproduct can be isolated either as the 6B-epimer or the aforesaidmixtures of 6aand 6fi-epimers, or a 60:- epimerized product can beobtained by treatment of the 6fi-epimer or mixtures of the 6aand6fl-epimers at temperatures of near zero degrees centigrade, in anorganic solvent, such as chloroform, methylene chloride. ether, and thelike, and in the presence of a prototropic agent (proton-donatingreagent) such as alcohols, organic acids,

and the like, with a hydrogen halide such as hydrogen chloride gas. Themixture should be maintained at temperatures near zero degreescentigrade although slightly higher or lower temperatures can be used,during the addition of the acid. The reaction mixture can then be washedwith successive portions of dilute alkali and water, and then dried andevaporated under reduced pressure. The Ga-flllOIO products can berecovered from the crude reaction product and purified byrecrystallization.

Alternatively, the epimerization can be accomplished with alkali. Bases,for example, solutions of sodium hydroxide and potassium hydroxide, maybe used to treat the 6fl-epimer in solution in an organic solvent, suchmethanol, to produce the fiwepimer.

GROUP B The novel Gu-fiuoro and 6fi-fluoro steroid compounds of Group(B) of the present invention,.2a-methyl-6-fluoro-9a-halo-11-oxygenated-17u,21 dihydroxy-4-pregnene-3,20-diones andthe 21-acy1ates thereof, for example2a-methyl-6-fluoro-9u-halo-11B,17a,21-trihydroxy-4- pregnene-3,20-dionesand2a-methyl-6-fluoro-9u-halol7a,21-dihydroxy-4-pregnene-3,11,20-triones,and the 17-, acylates thereof, are represented by the followingforwherein X and R have the meanings previously given, and Y is halogen.

The compounds of Group (B) of the present invention can be prepared inaccordance with the following reactions.

CH3 CH3 (IJHgOR 01120 R ----on ----on no CE I CHr- CH3" VII VIII CH3 CHCIIH OR C11 R CH5 811 -8H O Y CH3 CH:-- CH E E F F X IX XIV XIII whereinR has the meanings previously given, Y is bromo, chloro or iodo, and Y"is fluoro, chloro or bromo.

The process for preparing Group B compounds is carried out generally inaccordance with processes for preparing 9ot-halohydrocortisone andcomprises first the dehydration of2a-methyl-6-fluoro-11B,17a,21-trihydroxy- 4-pregnene-3,20-dione2l-acylate to obtain 2a-methyl-6- fluoro-l 7a,2 l-dihydroxy-4,9( l l)-pregnadiene r 3,20-dione 2l-acylate, followed by treatment of thedehydration product with a source of hypohalous acid in which thehalogen is bromine, chlorine, or iodine to produce the corresponding2a-methyl-6-fiuoro-9a-halo-11}9,17oc,21-tlihydroxy-4-pregnene-3,20-dione 21-acylate. The said halocompound is then epoxidized with a mild base to give2a-methyl-6-fluoro-9B,11fi-oxido-l7u,2l-dihydroxy-4- pregnene-3,20-dione21-acylate. Halogenation of the said 9,11-oxido compound, thehalogenating agent being one which provides a source of fluorine,chlorine or bromine, gives the corresponding 2a-methyl-6-fiuoro-9whalo-115,17u,21-trihydroxy-4-pregnene 3,20 dione 2'1- acylate. Uponhydrolysis of the said 9ot-halo 21-acylate there is producedZea-methyl-6-fluoro-9a-halo-11B,17a,21-trihydroxy-4-pregnene-3,20-dione, which can be oxidized by known methodsto produce.2a-methyl-6-fluoro-9ahalo- 2 l-dihydroxy-4-pregnene-3, l1,2-0-trione. Alternatively, 2u-methyl6-flHO1'0-9a-h3lO-11fi,17a,21-flihydroxy-4-pregnene-3,20-dione2l-acylate can be oxidized to produce the2a-methyl-6-fluoro-9a-halo-17u,21-dihydroxy-4-pregnene3,l1,20-trione 21acylate, which can-be hydrolyzed to give the Zen-methyl-6-fluoro-9a-halol7a, 2 l-dihydroxy-4-pregnene-3 l 1,20-trione.

The starting steroids for the process of preparation of the compounds ofGroup ('B) of the present invention are 2u-methy1-6a-fluoro-1l8,l7a,2l-trihydroxy 4 pregnene-3,2 0-dione 21-acyla'te and 2a-methyl-68-fluoro-l1p, l70;,21-trihydroxy-4-pregnene-3,2O-dione 21-acylate whichare prepared in accordance with the procedures disclosed in ourcopending application Serial No. 699,508, filed November 29, 1957, nowPat. No. 2,838,502, and disclosed in Preparation 1 below.

In carrying out this novel process of this invention,2a-methyl-6-fluoro-l1B,17a,21-trihydroxy 4 pregnene- 3,20-dione2l-acylate (VII) is dehydrated to the corresponding 21-acylate of2a-methy1-6-fluoro-17a,21-dihydroxy-4,9(l1)-pregnadiene-3,20-dione(VIII) by methods known in the art, e.g., by a dehydrating agent such asphosphorous oxychloride, thionyl chloride, hydrochloric acid or sulfuricacid and acetic acid or by pyrolysis as shown in US. Patents 2,640,838and 2,640,839, or the dehydration can be effected by the preferredmethod of reacting the 2a-methyl-6fiuoro-1lp,l7a,2l-trihydroxy4-pregnene-3,20-dione 2l-acylate with a carboxylic acid N- haloamide orN-haloimide, wherein the halogen is bromine or chlorine, in an organicbase either with or followed by anhydrous sulfur dioxide. Examples ofsuch N-haloamides or N-haloimides are N-chloroacetamide,N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide,3-bromo-5,S-dimethylhydantoin, 1,3-dibromo- 5,5-dimethylhydantoin andthe like, N-bromoacetamide being preferred. The organic bases employedas solvents in the above reaction are generally tertiary amines whereinthe amino nitrogen is a member of an aromatic ring, such as thepyridines and lower fatty amides, pyridine being preferred. Normally anamount in excess of molar equivalent of organic base calculated on thebasis of the quantity of starting steroid is employed. The sulfurdioxide is advantageously employed in substantially anhydrous form,inasmuch as the presence of water tends to decrease the yield ofdehydrated product. The temperature of the reaction is generally betweenminus forty and plus seventy degrees centigrade, the lower limit beingdetermined by the solubility of the substituents in the solvent selectedand the upper limit by the amount of side reaction which normallyaccompanies reactions involving halogen compounds at highertemperatures. Ordinarily, room temperatures are preferred forconvenience and because of the consistently high yields of end productwhich are obtained. A reaction time between about five minutes and threehours is usually employed, the specific temperature at which thereaction is conducted being determinative of the reaction time.

The thus-obtained dehydration product is converted to 2m methyl 6 fluoro9a halo 11152171121 trihydroxy-4-pregnene-3,20-dione 2l-acylate (IX) byreaction with a hypohalous acid. The hypohalous acid is usually producedin situ by reaction of an acid with N-haloamide or N-haloimide whereinthe halogen is bromine, chlorine or iodine. The2a-methyl-6-fluoro-l7a,21-dihydroxy-4, 9(11)-pregnadiene-3,20-dione2l-acylate is dissolved in an organic solvent such as methylenechloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol or thelike, and reacted at room temperature with the hypohalous acid releasingagent, which includes N-bromoacetamide, N- chloroacetamide,N-bromosuccinimide, N-iodo-succinimide, N-chlorosuccinimide, and thelike, in the presence of an acid such as perchloric acid, dilutesulfuric acid, and the like. N-bromoacetamide in tertiary butyl alcoholwith perchloric acid and water are the preferred reagents for thisreaction. Normally the halogenation is conducted at room temperatures,between fifteen and thirty degrees centigrade, although temperatures oneither side of this range are operative. The reaction period may varyfrom about five minutes to one hour. At the conclusion of the desiredreaction, the excess hypohalous acid is destroyed by the addition ofsulfites or hydrosulfites, sodium sulfite being normally employed. Theresulting 2ot-methyl-6- fluoro 90c halo 11B,17or,21 trihydroxy 4pregnene- 3,20-dione 2l-acylate (IX), in which the halogen is bromine,chlorine, or iodine, can be isolated from the reaction mixture by addingan excess of water and extracting the product with organic solvents orby recovering the precipitated compound by filtration, or the crudereaction product may be employed directly in the next step of theprocess.

The 9a-halo compound (IX) as defined above is then epoxidized with aWeak base, potassium acetate being preferred. The reaction is conductedin an inert solvent such as methanol, ethanol, acetone, dioxane, carbontetrachloride, chloroform, and the like. The epoxidizing reaction takesplace over a rather wide range of temperatures, normally from aboutminus fifteen degrees to the boiling point of the reaction mixture, therange between zero degrees and sixty degrees centigrade being mostconvenient. The reaction time may be varied considerably, depending onthe temperatures employed, a period of reflux of from about eight totwenty hours producing satisfactory yields, with about eighteen hoursusually being sufficient. The reaction mixture is concentrated, cooledand precipitated With water to give2a-methyl-6-fiuoro-9fl,llfi-oxido-l7u,2l-dihydroxy-4-pregnene-3,20-dione 2l-acylate (X).

In the epoxide opening step, the 9,1l-oxido compound (X) is reacted withan acid halide such as hydrogen fluoride, hydrogen chloride or hydrogenbromide, hydrogen fluoride being preferred, to produce the corresponding2amethyl 6 fiuoro 9a halo 11B,17a,21 trihydroxy 4- pregnene-3,20-dione21-acylate. The epoxide opening and halogenation is usually conducted attemperatures between about minus forty and plus fifty degreescentigrade, the preferred limits being between about zero and 25 degreescentigrade. Advantageously, the steroid is first dissolved in an organicsolvent such as tetrahydrofuran, methylene chloride, and the like. Inthe course of the foregoing reaction, it is possible that somehydrolysis of the 2l-acylate occurs, rendering the product somewhatdifiicult to recover by conventional methods, such as by chromatography.It is therefore preferable at the conclusion of the epoxide openingreaction to 2l-acylate the product by methods commonly employed foracylating steroids, such as by treatment with the appropriate anhydrideor acid halide of an organic carboxylic acid containing from one totwelve carbon atoms, inclusive, under conventional esten'fyingconditions. The halogenation reaction is operative at room temperaturesbut is preferably conducted at lower temperatures, such as zero to minuseighty degrees centigrade, with continuous stirring. The reaction timeis usually from about one to 24 hours, with one to five hours beingrequired at room temperatures. After the reaction is complete, themixture is poured into water and neutralized with a dilute base, such asdilute sodium or potassium hydroxide, or a bicarbonate such as sodiumbicarbonate, potassium bicarbonate, or the like. The reaction mixture isthen extracted in the usual manner, such as with methylene chloride, andthe 2a methyl 6 fiuoro 91x halo ll,6,l7a,21-trihydroxy-4-pregnene-3,20-dione 2l-acylate (XI) recovered in a purified form byrecrystallization or chromatography.

The 2a-methyl-6-fluoro-9a-halo-1 lfi,17m,2l-tril1ydroxy-4-pregnene-3,20-dione 2l-acylate (Xi), wherein the halogen is fiuorine,bromine, or chlorine, is then hydrolyzed to the free 21-alcohol (XII) inaccordance with known methods for hydrolyzing hydrocortisone 2l-estersto free hydrocortisone. A preferred procedure is to employ at least amolar equivalent of an alkali metal bicarbonate, such as potassiumbicarbonate, in a substantially oxygenfree solution of a mixture of alower alkanol, such as methanol, and water. The hydrolysis reaction isnormally conducted at temperatures between about ten and thirty degreescentigrade while protecting the mixture from atmospheric oxygen,generally by bubbling nitrogen continuously through the reactionmixture. After hydrolysis is complete, the mixture is neutralized withan acid such as acetic acid, dilute hydrochloric acid, or the like, andthe hydrolyzed product recovered by evaporation and crystallization,extraction with methylene chloride, or by other conventional methods.

The step of hydrolysis can be followed by reesterfication of the21-hydroxy group, as it is convenient to start with the 21-acetate asthe 21-acylate and thus carry the 2l-acetate through the synthesissteps. Esterification is carried out to produce the desired final2l-acylate using the appropriate anhydride or acid halide of an organiccarboxylic acid containing from one to twelve carbon atoms, inclusive,preferably of a hydrocarbon carboxylic acid, under conventional2l-acylating conditions. The thus produced Za-methyl-6-fluoro-9a-ha1o-11p,17,21-trihydroxy-4-pregnene-3,ZO-dione ZI-acylate can be oxidized tothe ll-keto compound (XIV) as described below.

The 20: methyl 6 fluoro 90c halo1113,17u,2ltrihydroxy-4-pregnene-3,ZO-dione (XII) can be oxidized to thecorresponding Za-methyl-6-fluoro-9u-halo-170;,21-dihydroxy-4-pregnene-3,l1,20-trione (XIII) by methods which efiect aselective oxidation at the ll-position, such as the procedure describedin U.S. Patent 2,751,402. In accordance with the procedure thereindescribed, selective oxidation is'accompl-ished by reaction of the 1118-hydroxy steroid with an N-haloamide or N-h-aloimide such asN-bromoacetarnide in a substantially nonreactive organic solventcontaining an amine, preferably tertiary butyl alcohol as the solventand pyridine as the amine.

Alternatively, the 2ot-methyl-6-fluoro 9a-halo-115,170,2l-trihydroxy-4-pregnene-3,20-dione 21-acylate (X1), instead of beinghydrolyzed as indicated above, can be first oxidized to thecorresponding ll keto compound ()GV) by known methods for convertinghydrocortisone acylates to cortisone acylates, such as by reaction Wit-hchromic acid. The thus-produced2ot-methyl-6-fluoro-9ahalo-17a,2l-dihydroxy-4-pregnene-3,1 1,20-trione21-acylate (XIV) can then be hydrolyzed as described above for thehydrolysis of the llfl-hydroxy-Zl-acylated steroid to yieldZea-methyl-6-fluoro-9a-halo-l7a,2l-dihydroxy-4- pregnene-3,11',20-trione(XIH) The foregoing compounds VII through XIV are all characterized bythe presence of a G-fluoro substituent. It should be noted that theconfiguration of the fluorine at the 6-position can be either 6a or 613.Thus substituting 2oz methyl 6B fluoro 1 lB,l7ot,2l trihydroxy 4-pregnene-3,20-dione as the starting steroid (VII) and following theprocedures hereinbefore described and as exemplified below, whilemaintaining near neutral reaction conditions, there is produced as thefinal product of each example the corresponding 6fi-epimer. Where the618- epimer or mixtures predominating therein is employed as thestarting material, any subsequent reaction product can be isolatedeither as the 6fi-epimer or the aforesaid mixtures of 60c- "and6/8-epimers, or a Ga-epimerized product can be obtained by treatment ofthe 6fl-epimer or mixtures of the 61 and 6B-epimers in an essentiallyanhydrous liquid medium with an anhydrous mineral acid, such ashydrochloric acid, in the presence of alcohol. For the most eflicientepimerization, the 6fi-product should be maintained below roomtemperatures, preferably below zero degrees centigrade, during theaddition of the acid. The reaction mixture can then be washed withsuccessive portions of dilute alkali and water and dried under reducedpressure. The corresponding 6ozproduct can then be purified byrecrystallization.

GROUP The novel 6a-flll01'0 and 6,8-fiuoro steroid compounds of Group(C), of the present invention 2-methyl-6- fluoro 9a halo 11 oxygenated1712,21 dihydroxy-l, 4-pregnadiene-3,20-diones and the Zl-acylatesthereof, for example, 2 methyl 6 fiuoro 9a halo l1/3,l7a,21trihydroxy-l, 4-pregnadiene-3,20-diones and 2-methyl-6- fluoro 9a halo17u,21 dihydroxy 1,4 pregnadiene- 3,11,20-triones, and the Zl-acylatesthereof, are represented by the following formula:

CHzOR cm I =0 wherein X, R and Y have the meanings previously: given."

CHa

XIX xvrrr CH; CH:

onion CIJHzOH (|J=O 1=o Y]! YII CH5," CH3 CH3 CH -v oo E E F F XX XXIon, on;

---o11 ---orr 0- O=/\ CH3 CH3 CH CH3 XXIII XXII wherein R, Y and Y havethe meanings previously given.

The process of preparing compounds of Group C is carried out inaccordance with processes for preparing 1,4-pregnadiene-3,,20-dione21-acylate to obtain Z-methyl- 6 -;fluoro 17,21-dihydroxy-1,4,9(11)-pregnatriene-3,20:

11 V dione 21-acylate, followed by treatment of the dehydration productwith a source of hypohalous acid in which the halogen is bromine,chlorine, or iodine to produce the corresponding2-methyl-6-fluoro-9a-halo-11,6,17a,2ltrihydroxy-l,4-pregnadiene-3,20-dione21-acylate. The said 9u-halo compound is then epoxidized with a mildbase to give 2-methyl-6-fluoro-9fi,llfi-oxido-17u,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acylate.Halogenation of the said 9,11-oxido compound, the halogenating agentbeing one which provides a source of fluorine, bromine or chlorine,gives the corresponding 2-methyl-6- fluoro 9ahalo-1lfi,1705,2l-trihydroxy-1,4-pregnadiene- 3,20-dione 21-acylate.Upon hydrolysis of the said 90:- halo 21-acylate there is produced2-methyl-6-fluoro-9ahalo 1 1,8,17a,21trihydroxy-l,4-pregnadiene-3,20-dione, which can be oxidized by knownmethods to produce the 2methyl-6-fluoro-9a-halo-1711,21-dihydroxy-1,4-pregnadiene-3 ,11,20-trione.

The starting steroids for the compounds and processes of Group (C) ofthe present invention are 2-methyl-6afiuoro1l5,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acylate andZ-methyl-fl-fluorodlfi,l7a,21-trihydroxy- 1,4- pregnadiene-3,20-dione2/1-acylate prepared in part (A), above.

In carrying out this novel process of this invention,2-methyl-6-fiuoro-1 lQ,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dioneZI-acylate (XVI) is dehydrated to the corresponding 21-acylate of2-methyl-6-fluoro-17a,2l-dihydroxyl,4,9(ll)-pregnatriene-3,20-dione(XVII) by methods known in the art, e.g., by a dehydrating agent such asphosphorous oxychloride, thionyl chloride, hydrochloric acid or sulfuricacid and acetic acid or by pyrolysis as shown in US. Patents 2,640,838and 2,640,839, or the dehydration can be effected by the preferredmethod of reacting the2-methyl-6-fluoro-llfl,l7oc,2ltrihydroxy-1,4-pregnadiene-3,20-dione21-acylate with a carboxylic acid N-haloamide or N-haloimide, whereinthe halogen is bromine or chlorine, in an organic base together withanhydrous sulfur dioxide. Examples of such N-haloamides or N-haloimidesare N-chloroacetarnide, N- bromoacetamide, N-chlorosuccinimide,N-bromosuccinimide, 3 -bromo-5,5-dimethylhydantoin, l,3-dibromo-5,5-dimethylhydantoin, and the like, N-bromoacetamide being preferred. Theorganic bases employed as solvents in the above reaction are generallytertiary amines wherein the amino nitrogen is a member of an aromaticring, such as the pyridines and lower fatty amides, pyridine beingpreferred. Normally an amount in excess of a molar equivalent of organicbase calculated on the basis of the quantity of starting steroid isemployed. The sulfur dioxide is advantageously employed in substantiallyanhydrous form, inasmuch as the presence of water tends to decrease theyield of dehydrated product. The temperature of the reaction isgenerally between minus forty and plus seventy degrees centigrade, thelower limit being determined by the solubility of the substituents inthe solvent selected and the upper limit by the amount of side reactionwhich normally accompanies reactions involving halogen compounds athigher temperatures. Ordinarily, room temperatures are preferred forconvenience and because of the consistently high yields of end productwhich are obtained. A reaction time between about five minutes and threehours is usually employed, the specific temperature at which thereaction is conducted being determinative of the reaction time.

The thus obtained dehydration product is converted to 2 methyl 6fiuoro-9 -halo-ll fi,17ot,21-trihydroxy-1,4- pregnadiene-3,20-dioneZl-acylate (XVIII) by reaction with a hypohalous acid. The hypohalousacid is usually produced in situ by reaction of an acid with anN-haloamide or N-haloimide wherein the halogen in bromine, chlorine oriodine. The2-methyl-6-fluoro-17u,21-dihydroxy-l,4,9(1l)-pregnatriene-3,20-dione21-acylate is dissolved in an organic solvent such as methylenechloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol or thelike, and reacted at room temperature with the hypohalous acid releasingagent, which includes N-bromoacetamide, N-chloroacetamide,N-bromosuccinimide, N- iodosuccinimide, N-chlorosuccinimide, and thelike, in the presence of an acid such as perchloric acid, dilutesulfuric acid, and the like. N-bromoacetamide in tertiary butyl alcoholwith perchloric acid and water are the preferred reagents for thisreaction. Normally the halogenation is conducted at room temperatures,between fifteen and thirty degrees centigrade, although temperatures oneither side of this range are operative. The reaction period may varyfrom about five minutes to one hour. At the conclusion of the desiredreaction, the ex cess hypohalous acid is destroyed by the addition ofsulfites or hydrosulfites, sodium sulfite being normally employed. Theresulting 2-methyl-6-fluoro-9a'halo-l13,1701, 21 trihydroxy 1,4pregnadiene-3,20-dione 21-acylate (XVIII), in which the halogen isbromine, chlorine or iodine, can be isolated from the reaction mixtureby adding an excess of water and extracting the product with organicsolvents or by recovering the precipitated compound by filtration. Thecrude material (XVIII) can be employed directly in the next step of theprocess.

The 9a-halo compound (XVIII) as defined above is then epoxidized with aweak base, potassium acetate being preferred. The reaction is conductedin an inert solvent such as methanol, ethanol, acetone, and the like.The epoxidizing reaction takes place over a rather wide range oftemperatures, normally from about minus fifteen degrees to the boilingpoint of the reaction mixture, the range between zero degrees and sixtydegrees centigrade being most convenient. The reaction time may becarried considerably, depending on the temperatures employed, a periodof reflux of from about eight to twenty hours producing satisfactoryyields, with about eighteen hours usually being sufficient. The reactionmixture is concentrated, cooled and precipitated with water to give 2-methyl 6 fluoro 95,1lB-oxido-l7a,21-dihydroxy-l,4-pregnadiene-3,20-dione 21-acylate (XIX).

In the epoxide opening step, the 9,11-oxido compound (XIX) is reactedwith an acid halide such as hydrogen fluoride, hydrogen chloride orhydrogen bromide, hydrogen fluoride being preferred, to produce thecorresponding 2-methyl-6-fluoro 9a halo 11fl,17a,2l tn'hydroxy 1,4pregnadiene 3,20 dione 21 acylate. The epoxide opening and halogenationis usually conducted at temperatures between about minus forty and plusfifty degrees centigrade, the preferred limits being between about zeroand 25 degrees centigrade. Advantageously, the steroid is firstdissolved in an organic solvent such as tetrahydrofuran, methylenechloride, and the like. In the course of the foregoing reaction, it ispossible that some hydrolysis of the 2l-acylate occurs, rendering theproduct somewhat diflicult to recover by conventional methods, such asby chromatography. It is therefore preferable at the conclusion of theepoxide opening reaction to 21-acylate the product by methods commonlyemployed for acylating steroids, such as by treatment with theappropriate anhydride or acid halide of an organic carboxylic acidcontaining from one to twelve carbon atoms, inclusive, underconventional esterifying conditions. The halogenation reaction isoperative at room temperatures but is preferably conducted at lowertemperatures, such as zero to minus eighty degrees centigrade, withcontinuous stirring. The reaction time is usually from about one to 24hours, with one to five hours being operative at room temperatures.After the reaction is completed, the mixture is poured into water andneutralized with a dilute base, such as dilute sodium or potassiumhydroxide, or a bicarbonate such as sodium bicarbonate, potassiumbicarbonate, or the like. The reaction mixture is then extracted in theusual manner, such as with methylene chloride, and the2-methyl-6-fluoro-9a-halo-11fl,17a,21-trihydroxy-1,4-pregnadiene-3,20dione 2l-acylate (XX) recovered in a purified form by recrystallizationor chromatography.

The 2-methyl-6-fluoro-9a-halo-1lfl,l7a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 2l-acylate (XX), wherein the halogen isfluorine, bromine, or chlorine, can then'be hydrolyzed to the free2l-a1cohol.(XXI) in accordance with knownmethods for hydrolyzinghydrocortisone 21- esters to free hydrocortisone. A preferred procedureis to employ at least a molar equivalent of an alkali metal bicarbonate,such as potassium bicarbonate, in a substantially oxygen-tree solutionof a mixture of a lower alkanol, such as methanol, and water. Thehydrolysis reaction is normally conducted at temperatures between aboutten and thirty degrees centigrade while protecting the mixture fromatmospheric oxygen, generally by bubbling nitrogen continuously throughthe reaction mixture. After hydrolysis is complete, the mixture isneutralized with an acid such as acetic acid, dilute hydrochloric acid,or the like, and the hydrolyzed product recovered by evaporation andcrystallization, extraction with a waterimmiscible solvent such asmethylene chloride, or by other conventional methods.

The step of hydrolysis can be followed by re-esterification of the21-hydroxy group, as it is convenient to start with the 2l-acetate asthe 2l-acylate and thus carry the 21-acetate through the synthesissteps. Esterification is carried out to produce the desired finalZl-acylate using the appropriate anhydride or acid halide of an organiccarboxylic acid containing from one to twelve carbon atoms, inclusive,preferably of a hydrocarbon carboxylic acid, under conventional2l-acylating conditions. The thus produced2-methyl-6-fiuoro-9a-halo-llfl,l7a,2l-trihydroxy-l,4-pregnadiene-3,20dione21-acylate can be oxidized to the'll-keto compound (XXIII) as describedbelow.

The 2-methyl-6-fluoro-9u-halo-1 15,17 a,2l trihydroxy-1,4-pregnadiene-3,20-dione ()QCI) can be oxidized to the corresponding2-methyl-6-fluoro-9u halo l7a,21 dihydroxy-l,4pregnadiene-3,l1,20-trione (XXII) by methods which effect a selectiveoxidation at the ll-position, such as the procedure described in U.S.Patent 2,751,402. In accordance with the procedure therein described,selective oxidation is accomplished by reaction of the 1113- hydroxysteroid with an N-haloarnide or N-haloimide such as N-bromoacetamide ina substantially nonreactive organic solvent containing an amine,preferably tertiary butyl alcohol as the solvent and pyridine as theamine.

Alternatively, the 2-methyl-6-fluoro-9a-halo-1 113,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione 2l-acylate (XX), instead of beinghydrolyzed as indicated above, can be first oxidized to thecorresponding ll-keto compound (XXIII) by known methods for convertinghydrocortisone acylates to cortisone acylates, such as by oxidation withchromic acid. The thus produced2-methyl-6-fluoro-9ahalo-17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione21- acylate (XXIII) can then be hydrolyzed as described above for thehydrolysis of the llfi-hydroxy-Zl-acylated steroid to yield2-methyl-6-fluoro-9a-halo-17a,2.l-dihydroxyl ,4-pregnadiene-3,11,20-trione (XXJI) The foregoing compounds XVI through XXIII are allcharacterized by the presence of a 6-fluoro substituent. [It'should benoted that the configuration of the fluorine at the 6-position can beeither 60: or 613. Thus substituting 2-methyl-6fl-fluoro-11fi,17u,21trihydroxy 1,4- pregnadiene-3,20-dione as the starting steroid (XVI) andfollowing the procedures hereinbefore described and as exemplifiedbelow, while maintaining near neutral conditions, there is produced asthe final product of each example the corresponding 6flepimer. Where the6pepimer or mixtures predominating therein is employed as the startingmaterial, any subsequent reaction product can be isolated either as the6fi-epimer or the afore-said mixtures of 60:. and 6B epimers, or a6a-epimerized prodnot can be obtained by treatment of the 613-epimer or14 7 mixtures of 60a and 6,8 epimers in an essentially anhy; drousliquid medium with an anhydrous mineral acid, such as hydrogen chloridein the presence of alcohol. For the most efficient epimerization, the6,8-product should be maintained below room temperatures, preferablybelow zero degrees centigrade, during addition of the acid. The reactionmixture can then be washed with successive portions of dilute alkaliand. water and dried under reduced pressure. The corresponding6a-product can then be purified by recrystallization.

GROUP D The novel 6a-fluoro and 6fi-fiuoro steroid compounds of Group(D) of this invention, 2a-methyl-6-fluorodloxygenated-17a-hydroxy-4-pregnene-3,20-diones and the correspondingl-dehydro compounds, for example 20:

methyl 6 fluoro-l1p,17a-dihydroxy-4-pregnene 3,20 dione, 21x methyl 6fluoro-l7a-hydroxy-4-pregnene-3, 11,20-trione, 2methyl-6-fluoro-l1B,17u-dihydroxy 1,4 pregnadiene-3,20 dione, and2-methyl-6-fluoro-l7a-hydroxy-l,4-pregnadiene-3,l1,20-trione, arerepresented by the following formula:

vention can be prepared in accordance with the following reactions:

CHgOSOzR (IJH2OH CH CHa-- XXV L--OH (IIH: C=O "-011 HO HO CH CH E E F FXXX XXVIII CH3 CH3 CH1 (EH3 C=O C=O ----0H '----on O I CH CH CH CH3 E EF F XXXI XXIX wherein R is an organic radical, particularly ahydrocarbon radical containing from one to ten carbon atoms inclusive,such as methyl, ethyl, phenyl, tolyl, naphthyl, or the like, methylbeing preferred.

In accordance with the present invention, a Lat-methyl-6-fluoro-ll-oxygenated-170:,21 dihydroxy 4 pregnene- 3,20-dione, forexample 2a-methyl-6-fluoro-1lB,17a,21-trihydroxy 4 pregnene-3,20-dione(XXV) is treated with an organic sulfonyl halide to obtain thecorresponding 2l-ester ()QCVI), a ZI-alkyl or aryl sulfonate of2amethyl-6-fluoro 11B,17a,21 trihydroxy-4-pregnene-3, 20-dione. The said2l-alkyl or aryl sulfonate is next reacted with an iodinating agent toobtain the corresponding 2l-iodo steriod (XXVII), which is dehalogenatedwith a reducing agent to produce2a-methyl-6-fluoro-l1,8,17u-dihydroxy-4-pregnene-3,ZO-dione (XXVIII). Ifdesired, the 6-fluoro-2l-desoxy product above can be oxidized to give 2amethyl 6 fluoro17a-hydroxy-4-pregnene-3,1l, ZO-trione (XXIX).Alternatively, the ll-keto compound, corresponding otherwise to thestarting material can be employed to yield the product (XXIX),eliminating the oxidation step. In this alternative method, theintermediates corresponding to compounds (XXVI) and (XXVII) possess thell-keto group instead of the llhydroxy group.

Similarly, substitution of the lla-hydroxy compounds of the compounds ofFormula XXV as starting material in the above reaction scheme producesthe lla-hydroxy compounds corresponding otherwise to the compounds ofFormulae XXVI through XXVIII. These 1lu-hydroxy compounds correspondingotherwise to Formula XXVIII can be oxidized in like manner to yield theproducts of Formula XXIX.

The selected 2u-methyl-6-fluoro-l15,170: dihydroxy-4 pregnene-3,20-dioneor 2a-methyl-6-fluoro-l7a hydroxy 4-pregnene-3,11,20-trione thusproduced, is l-dehydrogenated by fermentive or chemical dehydrogenationto pro duce the corresponding 2-methyl-6-fluoro-llfi,l7a dihydroxyl,4-pregnadiene-3,20-dione (XXX), or the corresponding 2methyl-6-fluoro-l7a-hydroxy-1,4-pregnadiene 15 3,11,20-trione (XXXI). Inlike manner, substitution of the lla-analogues of the compounds ofFormula XXVIII as starting material in the l-dehydrogenation reactionsis productive of the Ila-compounds corresponding otherwise to thecompounds of Formula (XIQQ.

The starting materials for Group (D) of the present invention are the2a-methyl-6-fluoro-11-oxygenated-17a,21-dihydroxy-4-pregnene-3,ZO-diones, for example,

2m-methyl-6a-fluoro-llp,17a,21 trihydroxy 4-pregnene 3,20-dione,

2a methyl-65 fluoro-115,17a,2l-trihydroxy-tpregnene 3,20-dione,

2ot-methyl-6a fluoro 17a,21 dihydroxy-4-pregnene-3,

11,20-trione, and

2a methyl 6 9 fluoro-,21-dihydroxy-4-pregnene-3,

l 1,20-trione,

prepared in accordance with the procedures disclosed in copendingapplication Serial No. 699,508 filed November 29, 1957, and Preparation1 described below.

In carrying out the process of this invention, Za-methyl 6 fluoro11B,l7a, 2l-trihydroxy-4-pregnene-3,ZO-dione (XXV) is treated with anorganic sulfonyl halide such as methanesulfonyl chloride,toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonylchloride, naphthylsulfonyl chloride, or the like, the methanesulfonicacid halides, especially methanesulfonyl chloride, being preferred. Inthe preferred embodiment of this invention, the starting sten'od isreacted with the alkyl or aryl sulfonyl halide in solution in a solventsuch as pyridine, benzene, toluene, or the like. Where such solvents asbenzene and toluene are employed, an amount of amine base such aspyridine at least equal to the molar amount of the sulfonyl halideshould also be present to react with the halogen acid formed. Reactionof the alkyl or aryl sulfonyl halide is conducted preferably at atemperature between minus ten and plus sixty degrees centigrade,provided that at the lower temperature the solvent has not solidified.Thus, for pyridine, dioxane, toluene or the like, temperatures in therange of zero to ten degrees centigrade can be used, while for benzeneonly temperatures above five degrees centigrade are suitable because ofthe relatively high melting point of benzene. The reaction time isusually between about thirty minutes and 24 hours, after which theproduct, 2a-methyl-6 fluoro l15,17a,2l-trihydroxy-4pregnene-3,ZO-dione21-alkyl or aryl sulfonate (XXVI), is recovered in a conventionalmanner, such as, for example, by evaporating the solvent until a solidresidue is obtained or by diluting the reaction mixture with water andprecipitating the product with dilute hydrochloric acid.

The 21-iodo compound (XXVII) is prepared by reacting the said 21-alkylor aryl sulfonate with an iodinating agent such as an alkali metaliodide, e.g., sodium, potassium or lithium iodide in an oxygenatedhydrocarbon solution, e.g., an alkanone solution such as acetone. Amolar excess of the iodide (three to twenty moles of iodide per mole ofsteroid) is generally preferred for this reaction. The reaction mixturecontaining the 2l-alkyl or aryl sulfonate and the alkali metal iodide insolution is heated to reflux for a period of about three to thirtyminutes. The thus produced 2m-methyl-6-fluoro-21-iodol1p,17a-dihydroxy-4-pregnene-3,20 dione (XXVII) can then be isolated byevaporating the solvent. For the subsequent reaction, the 21-iodocompound can be used either in purified form as a product ofrecrystallization from such organic solvents as acetone, ethanol, or thelike, or it can be employed directly as a crude product in the next stepof the synthesis.

The 20: methyl 6 fluoro 1lfl,17wdihydroxy-21-iodo 4-pregnene-3,20-dioneis dehalogenated at the 21-position by reaction with a reducing agentsuch as sodium or potassium thiosulfate, bisulfite or sulfite, or zincand acetic acid, or the like. In the preferred embodiment of the in--vention, the::crude 2l-iodide is slurried with-zinc-and saceticaci'cl'and -the mixture stirred at room-temperature for-a=p,eriod of fiveminutes'to two'hours. After dilution with water,-therproduct isisolated'from the reaction mixture by conventional methods, such as byfiltration orextraction with a water-immiscible organic solvent, e.g.,ether, benzene, methylene chloride, ethylene chloride, carbontetrachloride,"chloroform, hexane, 'heptane, or the -like,'-andevaporating the solvent therefrom. Purification of the thus obtained2a=methyl-6-'fluoro-1 15,17a dihydroxy-4-pregnene-3,20-dione (XXVIII)can be carried out -droXy-4-pregnene-3,20-dione can be carried out by avariety of methods, such as, for example, by oxidizing the said2u-methy-l-6 fluoro-2l-desoxy steroid in acetic acid solution withchromium trioxide, using molar quantities or a slightexcess, oremploying a haloamide or haloimide of an acid such as N-bromoacetamide,N-chlorosuccinimide, or N bromosuccinimide in pyridine, dioxane, orother solvent solutions. After conclusion of the desired oxidation, theoxidant is generally destroyed by addition of methyl alcohol, ethylalcohol, or the like when chromic acid is the oxidizing agent, and analkali bisulfite when N-bromosuccinimide or other N-haloacylimides oramides are used. Thereafter, 2a-methy1-6-fluoro-17a-hydroxy-4pregnene-3,l1,20-trione (XXIX) is recovered by conventional means, suchas extraction with water-immiscible solvents, e.g., methylene chloride,ethylene chloride, chloroform, carbon tetrachloride, ether, benzene,toluene and the like, or by chromatography.

In like-manner, substitution of 2ot-methyl-6-fiuoro-l'la,17a-dihydroxy-4-pregnene-3,20-dione as starting material in theoxidation reaction is productive of Zea-methyl '6fluoro-17u-hydr0xy-4-pregnene-3 1 1 ,ZO-trione.

The dehydrogenation of theselected 2a-methyl-6-fluoro-1l-oxygenated-l7a-hydroxy-4-pregnene-3,20-dione for example 2a-methyl 6fiuoro-l1,8,17a-hydrox3lpregnene-3, ZO-dione (XXVIII), and2a-methyl-6-fiuoro-17a-hydroxy- 4-pregnene-3,ll,20-trione (XXIX) toobtain the corresponding l-dehydro compounds for example 2-methyl-6fluoro-1l,6,l7u-dihydroxy 1,4-pregnadiene-3,20 dione (XXX) and2-methyl-6-fluoro-17a-hydroxy-1,4 pregnadiene-3,11,20-trione (XXXI) canbe carried out by fermentative or-chemical dehydrogenation.Microorganisms such as, for example, Septomyxa, Corynebacterium,Didymella, Calonectria, Alternaria, Colletotrichum, Cylindrocarpon,Ophiobolus, Fusarium, Listeria, Erysipelothrix, Mycobacterium,Tricothecium, Leptosphaeria, Cncurbitaria, Nocardia, and enzymes offungi of the family Tubenculariaceae can be used under fermentationconditions well known in the art (e.g., U.S. 2,602,769) and further moreillustrated by Examples 8D and 9D herein.

When Septomyxa is used to effect the dehydrogenation of the compounds ofFormula XXVIII it is advantageous to use with the substrate and medium asteriod promoter, such as, progesterone, 3-ketobisnor-4-cho1en-22-al,3-ketobisnorcholenic acid, 11B,21-dihydroxy,1,4,17 -pregnatrien-3-one,and the like.

The chemical dehydration can be carried out with selenium dioxideaccording to known procedures [e.g., Meystre et al., Helv. Chim. Acta,39, 734 (1956)].

In the foregoing processes, it should be understood that either the6oc-fil1010 epimer -or the 6fl-fluoro epimer can be utilized at anystage. The 6u-epimer can be obtained at appropriate intermediate stagesby treatment of the 6 3-compound, at temperatures of zero degreescentigrade or slightly lower and in an organic solvent such as chloro-18 form, with an anhydrous mineral acid, such as hydrochloric acid, inthe presence of alcohol. Such temperatures should be maintainedthroughout the period of addition of the acid. The reaction mixture canthen be washed with successive portions of dilute alkali and water andevaporated under reduced pressure to obtain the epimerinhigh yield.

GROUP E The novel 6u-fluoro and 613-fluoro steroid compounds of Group(E) of this invention, 2a-metyl 6,2ldifluoro 1l-oxygenated17u-hydroxy-4rpregnene-3,20 diones and the corresponding l-dehydrocompounds, for example, Zea-methyl 6,21difluoro-11,8,l7u-dihydroxy-4-pregnene 3,20-dione, 2oz methyl 6 ,21difluoro l7a-hydroxy 4-pregnene-3,

1'l,20:-trione,

2 methyl 6,2l-difluoro-11/3,17ot dihydroxy-1,4-pregnadiene-3,20-dione,and 2-methyl 6,21 difluoro 17cc hydroxy-l,4-pregnadiene 3,11,20-trione aare reprwented by the followingformula:

CHa

(IJH2F C=O ---on XXXII wherein X has the meaning previously given andthe 1,2- carbon atom'linkage is selected from the linkages consisting ofsingle bond and double bond linkages. The novel compounds of Group (E)of the present invention can be prepared in "accordance with thefollowing reactions:

CH: CH:

CHzF (I'JH2F C C:

wherein R has the meanings previously given The process of Group (E) ofthis invention comprises treating a 21-alkyl or aryl sulfonate of2u-methy1-6-fluoro 1l-oxygenated-17a,21-dihydroxy 4 pregnene-3,20-dione,for example, a 21-alkyl or aryl sulfonate of20amethyl-6-fiuoro-1lp,17a,21-trihydroxy 4 pregnene-3, 20-dione (XXXIII)with a fluorinating agent to obtain the corresponding2a-methyl-6,21-difluoro-115,1711 dihydroxy-4-pregnene-3,20-dione(XXXIV). If desired, the 2a-methyl-6,21-difluoro product above can beoxidized to give the corresponding2a-methyl-6,21-difluoro-17a-hydroxy-4-pregnene-3,11,20-trione (XXXV).Alternatively, 2a methyl 6 fluoro-11fi,l7adihydroxy-21-iodo-4pregnene-3,20-dione (XXXVIII) can be fluorinated to yield the 21-fluorosteroid (XXXIV). If the ll-keto compound corresponding otherwise to thecompound of Formula XXXIII is employed, the product (XXXV) is obtainedwithout the oxidation step.

3 Similarly, substitution of the Ila-hydroxy compounds correspondingotherwise to Formulae XXXIH and XXXVIII as starting material in theabove reaction scheme produces the Ila-hydroxy compounds correspondingotherwise to Formula XXXIV which can be oxidized in the same manner asthe lip-hydroxy compounds to yield the products of Formula XXXV.

The selected Zea-methyl6,21-difluoro-11,9,17a-dihydroxy-4-pregnene-3,ZO-dione or2a-methyl-6,21-difluoro 17u-hydroxy-4-pregnene-3J1,20-trione thusproduced, is l-dehydrogenated by fermentative or chemicaldehydrogenation to produce the corresponding2-methyl-6,2l-difluoro-11fl,17u-dihydroxy-1,4-pregnadiene 3,20 dione(XXXVI), or 2-methy1-6,2l-difluoro-17a hydroxy 1,4 pregnadiene-3,1l,20trione (XXXVII). In the same manner, substitution of the 110: hydroxycompounds corresponding otherwise to Formula )O(XIV as starting materialin the l-dehydrogenation reactions is productive of the Ila-hydroxycompounds corresponding otherwise to Formula )O(XVI.

The starting materials for Group (E) of the present invention includethe 21-alkyl or aryl sulfonates of 2c: methyl 6fluoro-ll-oxygenated-17a,21-dihydroxy 4 pregnene-3,20diones (XXXIII) orthe 20: methyl 6 fluoro-ll-oxygenated-l7a hydroxy 21-iodo-4-pregnene3,20-diones (XXXVIII) for example 2a-methyl-6a-fluoro-11,6,17u,2l-trihydroxy-4-pregnene-3,20-dione 2l-methanesulfonate,2a-methyl-6fi,fiuoro-l1B,17a,2l-trihydroxy 4 pregnene-3,20-dione21-methanesulfonate, Zea-methyl 6a fiuoro-17a,2l-dihydroxy-4-pregnene3,11,20 trione 21 methanesulfonate, Zea-methyl 6B fluoro 17cc,21-dihydroxy 4 pregnene-3,1l,20-trione 21-methanesulf0- nate,2a-methyl-6a-fluoro 11,9, 17a-dihydroxy 21 iodo 4-pregnene-3,20 dione,2a-methyl-6fl-fluoro 1113,17oz-dihydroxy-21-iodo-4-pregnene-3,ZO-dione,2m methyl 6a fluoro-lh-hydroxy 21 iodo 4 pregnene-3,11,20-trione andZea-methyl 6,3 fluoro 17a-hydroxy-2l-iodo 4 pregnene-3,11,20-trioneprepared in Group (D), above, and represented in Group (D) by FormulaeXXVI and XXVII.

In carrying out the process of the present invention, 20: methyl 6fluoro ll-oxygenated 17u,21'dihydroxy-4-pregnene-3,20-dione 21-alkyl oraryl sulfonate, for example 2a-methy1-6-fluoro-11B,17a,21-trihydroxy-4-pregnene-3,20-dione 2l-alkyl or aryl sulfonate (XXXIII) is treated witha fluorinating agent such as potassium fluoride, silver fluoride orantimony fluoride in an inert solvent such as dimethylsulfoxide,acetonitrile, dimethylformamide or ethylene glycol solution, thepreferred combination being potassium fluoride in dimethylsulfoxide. Thereaction is advantageously conducted under continuous heating, and itproceeds generally for a period of about six to 24 hours, fifteen totwenty hours usually being suflicient. The reaction mixture is thendiluted with an organic solvent such as methylene chloride, chloroform,benzene, and the like, and purified in a conventional manner, as, forexample, by chromatography or solvent extraction to give thecorresponding 2a-methyl-6,21- difluoro l1 oxygenated 17oz hydroxy 4pregnene- 3,20-dione, for example, 2a-methyl-6,21-difluoro-115,170:-

tdihydroxy-4-pregnene-3,ZO-dione (XXXIV) Alternatively, a2a-methy1-6-fluoro-11-oxygenated-17ahydroxy-21-iodo-4-pregnene-3,20-dione,for example, 20:- methyl 6 fluoro1lfi,17a-dihydroxy-21-iodo-4-pregnene-3,20-dione (XXXVIII) dissolved ina solvent such as acetonitrile, dimethylformamide or ethylene glycol istreated with a metal fluoride such as silver fluoride, antimonyfluoride, potassium fluoride, or the like, acetonitrile and silverfluoride being preferred. The metal fluoride should be added in smallquantities at intervals, and the reaction mixture should be protectedfrom light during-the reaction period, which usually ranges from aboutone-half to six hours. The reaction mixture is then concentrated and theproduct extracted as in previous purification steps to yield thecorresponding 6,21-difluoro steroid, for example, 20: methyl 6,21difluoro-l1/3,17a-dihydroxy-4-pregnone-3,20-dione (XXXIV).

The foregoing reactions constituting either the principal or alternativeroutes can likewise be conducted on the corresponding ll-keto compounds,and the corresponding Ila-hydroxy compounds.

The oxidation of2a-methyl-6,21-difluoro-11,9,17a-dihydroxy-4-pregnene-3,ZO-dione (XXXIV)can be carried out by known methods, such as, for example, by oxidizingthe said 6,2l-difluoro steroid in acetic acid solution with chromiumtrioxide, using molar quantities or a slight excess, such as from ten tothirty percent excess, or by oxidizing with a haloamide or imide of anacid, such as N-bromoacetamide, N-chlorosuccinimide, orN-bromosuccinimide dissolved in pyridine, dioxane, or other suitablesolvents. At the conclusion of the oxidation reaction, the oxidant isgenerally destroyed by addition of methyl alcohol, ethyl alcohol, andthe like for the chromic acid oxidant or a bisulfite forN-bromoacetamide, N-bromosuccinimide and other N-halo acyl amides andimides. Thereafter, the resulting2a-rnethyl-6,21-difluoro-17a-hydroxy-4-pregnene-3,11,20-trione (X)Q V)is recovered by conventional means, such as by extraction withwaterimmiscible solvents, e.g., methylene chloride, ether, benzene,toluene or the like, or by chromatography.

p In the same manner, substitution of2a-methyl-6,21-difluoro-11a,17a-dihydroxy-4-pregnene-3,ZO-dione asstarting material in the oxidation reaction is productive of 2amethyl-6,2l-difluoro-17u-hydroxy4-pregnene-3,11,20- trione.

. The dehydrogenation of the selected 2a-methyl-6,21-di fluoro 11oxygenated 17a hydroxy 4 pregnene- 3,20-dione, for example2a-methyl-6,21-difluoro-115,170:-

known in the art (e.g., US. 2,602,769) and furthermore illustrated byExamples 4E and 5E herein.

When 20: methyl 6,21 difluoro-l lfi, l7ot-dihydroxy-4-pregnene-3,20-dione and2a-methyl-6,2l-difluoro-l10;,17adihydroxy-4-pregnene-3,20-dione are thestarting materials and Septomyxa is used toefiect the l-dehydrogeuationis is advantageous to use withthe substrate and-medium a steroidpromoter, such as progesterone, B-ketobisnor-4-cholen-22-al,3-ketobisnorcho1enic acid, 116,21-dihydroxy-l,4,l7(20)pregnatrien-3-one, and the like.

The chemical dehydrogenation can be carried out with selenium dioxideaccording to known procedures [eg., Meystre et al., Helv. Chim. Acta 39,734 (1956)].

In the foregoing processes, it should be understood that thecorresponding 6,3-fluoro epimer can be utilized at any stage and the6a-epimer obtained at appropriate intermediate stages by treatment ofthe 6fi-cornpound in an organic solvent such as chloroform, attemperatures of zero degrees centigrade or slightly lower, with ananhydrous mineral acid, such as hydrochloric acid, in the presence. ofalcohol. Such temperatures should be maintained throughout the period ofaddition of the acid. The reaction mixture can then be washed withsuccessive portions of dilute alkali and water and evaporated underreduced pressure to obtain the 6a-epimer.

The novel 6ct-fil10l0 and 6B-fluoro steroid compounds of Group (F) ofthis invention, 2u-methyl-6-fiuoro-9ahalo 11 oxygenated 17oz hydroxy 4pregnene 3, 20-diones and the corresponding l-dehydro compounds, forexample, 2a-methyl-6-fluoro-9u-halo-1lfi,l7a-dihydroxy 4 pregnene 3,20dione, 2a-methyl-6-fluoro- 90c halo 17 a hydroxy 4 pregnene 3,11,20-trione, 2 methyl 6 fluoro 90c halo 11 8,17 dihydroxy- 1,4 pregnadiene3,20 dione, and 2 methyl 6 fluo- 1'0 9a halo 17oz hydroxy 1,4pregnadiene 3,11, 20-trione are represented by the following formula:

wherein X and Y" have the meanings previously given, and the 1,2-carbonatom linkage is selected from the linkages consisting of single bond anddouble bond linkages.

The novel compounds of Group (F) of this invention can be prepared inaccordance :with the following reac- -tions:, v Y r g CHI 7 on: onion 65XLIV XIZVI wherein Y" and R have the meanings previously .given.Theprocess of Group (F) of the present invention comprises treating a2a-methyl-6-fluoroe9u-halo 1"1p,l7a, 21-nihydroxy-4-pregnene-3,20-dione(XL) with an organicsulfonyl halide to obtain the cor-responding2l-ester (XLI), and 2l-alkyl or aryl 'sulfonate of 2u-methy'1-6- fluoro9e: halo 1113,]70:,2'1*trihydroxy-4-pregnene 3, 2-0-dione, andthereafter treating the thus produced 21 alkyl or aryl sulfonate with aniodinating agent, such as i sodium iodide in acetone solution, to'obtain the corresponding 2a methyl 6 fluoro 90c halo 115,176:-dihydroxy-21-iodo-4-pregnene-3,ZO-dione (XLH) and, finally, treating thethus produced 2a-methyl-6-fluoro- 9oz halo 11,6,17a-dihydroxy 21 iodo 4pregnene- 3,20-dione with a reducing agent, such as zinc dust, sodiumthiosulfate, sodium bisulfite, potassium bisulfite, or the like,preferably in an aqueous organic solvent mixture, to obtain2a-methyl-6-fluoro-9a-halo-1l S,l7a-dihydroxy-4-pregnene-3,20-dione(XLIII). If desired, the 2a-methyl-6-fluoro-9a-halo product XLIII abovecan be oxidized to give the corresponding 2a-methyl-6-fluoro- 9a halo17a hydroxy '4 pregnene 3,11,20 trione (XLIV). Moreover, when thecorresponding ll-keto compound(Zn-methyl-6-fluoro-9a-halo-Hail-dihydroxy- 4pregnene-3,l1,20-trione) isutilized as starting material in the above series of reactions,2a-methyl-6- fluoro-9ahalo-17a-hydroxy-4-pregnene3,11,20-trione (XLIV)is produced directly without the necessity for oxidation of thellfi-hydroxyl as the final step.

The selectedZa-methyl-6-fluoro-9u-halo-l1p,17a-dihydroxy-4-pregnene-3,20-dione or2a-methyl-6-fluoro-9ahalo 17a hydroxy 4 pregnene 3,11,20 trione thusproduced, is l-dehydrogenated by fermentative or chemicaldehydrogenation to produce the corresponding 2- methyl 6 fluoro 9oz halo115,171 dihydroxy 1,4- pregnadiene-3,20-dione (XLV), or thecorresponding 2- methyl 6 fluoro 9a halo 17a hydroxy 1,4pregnadiene-3,11,20-trione (XLVI) The starting steroids for thecompounds and process of Group (F) of this invention include2a-methyl-6a-fluoro- 9a. halo 11,8,l7a,2l trihydroxy 4 pregnene 3,20-dione, 2a methyl 6B fluoro 9oz halo 1l/3,17ot,21- trihydroxy 4 pregnene3,20 dione, 20c methyl 6afluoro 9oz halo 17a,21 dihydroxy 4 pregnene-3,11,20-trione, and2a-methyl-6B-fluoro-9a-halo-l7u,21-dihydroxy-4-pregnene3,11,20-trioneprepared in Group (B), above.

In accordance with this invention, 2a-methyl-6-fluoro- 9oz halol1,8,17a,21-trihydroxy 4 pregnene 3,20- dione (XL) is treated with anorganic sulfonyl halide such as methanesulfonyl chloride,toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonylchloride, naphthylsulfonyl chloride, or the like, the methanesulfonylacid halides, especially methanesulfonyl chloride, being preferred. Inthe preferred embodiment of this invention, the starting steroid isusually reacted with the alkyl or aryl sulfonyl halide in solution in asolvent such as pyridine, benzene, toluene, or the like. Where suchsolvents as benzene and toluene are employed, an amount of an amine basesuch as pyridine at least equal to the molar amount of the sulfonylhalide should also be present to react with the hydrochloric acidformed. Reaction of the alkyl or aryl sulfonyl halide is conductedprefably at temperatures between minus ten and plus sixty degreescentigrade, provided that at the lower temperatures the solvent has notsolidified. Thus, for pyridine, dioxane, toluene, or the like,temperatures in the range of zero to ten degrees centigrade can be used,While for benzene only temperatures above five degrees centigrade aresuitable because of the relatively high freezing point of benzene. Thereaction time is usually between about four to 24 hours, after which theproduct, 2a-methyl-6 fluoro 9a halo 1lp,17ot,21 trihydroxy 4pregnene-3,20-dione 21-alkyl or aryl sulfonate (XLI), is recovered in aconventional manner, such as, for example, by evaporating the solventuntil a solid residue is obtained or by diluting the reaction mixturewith water and precipitating the product with dilute hydrochloric acid.

The 2a-methyl-6-fiuoro-9a-halo-l 1B,17a,21-trihydroxy-4-pregnene-3,20-dione 21-alkyl or aryl sulfonate is converted to thecorresponding 21-iodo compound (XLII) by reacting the said 21-alkyl, oraryl sulfonate with an iodinating agent, suchas an alkali metal iodide,e.g., sodium, potassium or lithium iodide,.in an oxygenated hydrocarbonsolution such as an alkanone solution, e.g., acetone. A molar excess ofthe iodide (three to twenty moles of iodide per mole of steroid) isgenerally preferred for this reaction. The reaction mixture containingthe 21-alkyl or aryl sulfonate and the alkali metal iodide in solutionis heated to reflux for a period of about three minutes to thirtyminutes. The thus produced Zen-methyl- 6 fluoro 9oz halo 21 iodo11fi,17a dihydroxy 4- pregnene-3,20-dione can then be isolated byevaporating the solvent. For the subsequent reaction, the 21-iodosteroid can be used either in purified form as a product ofrecrystallization from such organic solvents as acetone, ethanol, or thelike, or it can be employed directly as a crude product in the next stepof the synthesis.

In order to obtain2a-methyl-6-fluoro-9a-halo-11p,l7adihydroxy-4-pregnene-3,ZO-dione(XLIII), the crude 2amethyl 6 fluoro 9a. halo- 115,170; dihydroxy 21-iodo-4-pregnene-3,20-dione is reacted with a reducing agent such assodium or potassium thiosulfate, sodium bisulfite or zinc dust in aceticacid. In the preferred embodiment of the invention the 2l-iodo compoundis dissolved in acetic acid at room temperature and stirred from aboutthirty minutes to one hour. Excess aqueous sodium thiosulfate is added,followed by ice and water. The time of reaction is not critical and isgenerally between a few minutes and several hours. The amount of sodiumthiosulfate may be varied so long as an excess is used. .The product,2e-methyl-6-fiuoro-9a-ha1o-116,17- dihydroxy-4-pregnene-3,ZO-dione, isobtained by conventional means such as recrystallization or extractionand thereafter recrystallization or chromatography as deemed necessary.

The foregoing reactions can likewise be conducted on the correspondingll-keto compounds.

The oxidation of 20t-m6lhYl-6-flllOI'O-90t-h3l0-11fl,17t1-dihydroxy-4-pregnene-3,ZO-dione (XLIII) can be carried out by a varietyof methods, such as, for example, by oxidizing the said2a-methyl-6-fluoro-9a-halo-llB-hydroxy steroid in acetic acid solutionwith chromium trioxide, using molar quantities or a slight excess, suchas from ten to thirty percent excess, or by oxidizing with a haloamideor imide of an acid, such as N-bromoacetamide, N-chlorosuccinimide, orN-bromosuccinimide dissolved in pyridine, dioxane, or other suitablesolvents. At the conclusion of the desired oxidation reaction, theexcess oxidant is generally destroyed by the addition of methyl alcohol,ethyl alcohol, and the like for the chrornic acid oxidant, or abisulfite for N-bromoacetarnide, N- bromosuccinirnide and other N-haloacyl amides and imides. Thereafter, the resulting2a-methyl-6-fluoro-9ahalo-17a-hydroxy-4-pregnene-3,11,20-trione (XLIV)is recovered by conventional means, such as by extraction withwater-immiscible solvents, e.g., methylene chloride, ether, benzene,toluene or the like, or by chromatography.

The dehydrogenation of the selected 2a-methyl-6- fluoro 9oz halo11,8,17a dihydroxy 4 pregnene- 3,20-dione (XLIII), or2a-methyl-6-fluoro-9a-halo-17ahydroxy-4-pregnene-3,11,20-tri0ne (XLIV)to obtain the corresponding l-dehydro compounds 2-methyl-6-fluoro- 9ahalo 1l 3,l7oc dihydroxy 1,4 pregnadiene 3,20- dione (XLV) andZ-methyl-6-fiuoro-9a-halo-17a-hydroxy-1,4-pregnadiene-3,11,20-trione(XLVI) can be carried out by fermentative or chemical dehydrogenation.Microorganisms such as, for example, Septomyxa, Corynebacterium,Didymella, Calonectria, Alternan'a, Colletotrichum, Cylindrocarpon,Ophiobolus, Fusarium, Listeria, Erysipelothrix, Mycobacterium,Tricothecium, Leptosphaen'a, Cucurbitaria, Nocardia, and enzymes offungi of the family Tuberculariaceae can be used under fermentationconditions well known in the art (e.g., US. 2,602,769) and furthermoreillustrated by Examples 6F and 7F herein.

When Septomyxa is used to effect the dehydrogenation of the compounds ofFormula XLIH it is advantageous to use with the substrate and medium asteroid promotor,

'25 'Such as, progesterone, 3-ketobisnor-4-cholen-22 al, 3-ketobisnorcholenic acid, 11,8,21-dihydroxy-1,4,17(20)-pregnatrien-S-one, and the like.

The chemical dehydration can be carried out with selenium dioxideaccording to known procedures [e.g., Meystre et al., Helv. Chim.Acta'39, 734 (1956)].

Alternatively, if desired, removal of the oxygen at carbon atom 21 canbe accomplished first, and this can be followed by halogenation atcarbon atom 9. For example 20c methyl 6 fluoro 115,17 dihydroxy 4pregnen-3,20-'dione prepared in group (D), above, can be dehydrated withN-bromoacetamide and anhydrous sulfur dioxide in pyridine solution bypermitting the reaction to continue until a negative acidified potassiumiodide-starch test of the reaction mixture is obtained. Dilution withcold water results in the precipitation of 20: methyl 6 fluoro 17cchydroxy 4,9(11) pregnadiene-3,20-dione, which can be purified byrecrystallization from acetone. The crystalline product can then bereacted in methylene chloride-tertiary butyl alcohol solution withperchloric acid and N-bromo-acetamide or N-iodosuccinimide to produce areaction mixture from which2a-methyl-6-fluoro-9a-bromo-11B,17a-dihydroxy-4- pregnene-3,20-dione orthe corresponding 2a-methy1-6- fll101'0-9oc-i0d0 compound can berecovered by precipitation with ice water and recrystallization fromacetone. The latter compounds can then be reacted in acetone solutionwith anhydrous potassium acetate at reflux temperatures to produce2a-methy1-6-fluoro-9p,11,8-oxido- 17 ot-hydroxy-4pregnene-3,20-dione,which is recoverable from the reaction mixture by chromatography and canbe further purified by recrystallization from Skellysolve Bhexanes-acetone. Reaction of the said 9,11-oxido compound in methylenechloride solution with aqueous hydrogen fluoride or hydrogen fluoridegas in the presence of tetrahydrofuran at room temperature is productiveof 2a-methyl-6,9a-difiuoro-11/3,17a-dihydroxy-4-pregnene-3,20-dione.Substitution of aqueous hydrogen chloride for the hydrogen fluorideabove yields 2a-methyl-6- fluoro 9a chloro 115,17 dihydroxy 4 pregnene-3,20-dione. If desired, either the 9oz-fill0l0, chloro, bromo or iodoproduct can be oxidized, for example, with chromic acid in acetic acidsolution to give 211- methyl 6,90; difluoro 17oz hydroxy 4 pregnene-3,11,20-trione, the corresponding 906-011101'0 compound, thecorresponding 9a-bromo compound, or the corresponding 90c-i0d0 compound.

In like manner, substitution of 2-methyl-6-fluoro-1113,17a-dihydroxy-1,4-pregnadiene-3,20-dione prepared in Group (D), abovefor Za-methyl-fi-fluoro-l1,6,17wdihydroxy-4-pregnene-3,20-dione in theabove alternative process is productive of the corresponding 2-methy1-6-fluro 9oz halo 11 oxygenated 17oz hydroxy-1,4-pregnadiene-3,20-d.iones,for example 2-methyl-6,9a-difluoro-11,3,17a-dihydroxy-1,4-pregnadiene-3,ZO-dione, Z-methyl- 6,9a-difluoro-l7a-hydroxy-1,4-pregnadiene-3,1 1,20-trione, and theircorresponding 9wchl0ro, 9a-bromo and 9u-iodo analogues.

In the foregoing processes, it should be understood that thecorresponding 6 8-epimer can be utilized at any stage and the 6a-epimerobtained at appropriate intermediate stages by treatment of the6,8-compound, at temperatures of zero degrees centigrade or slightlylower, in an organic solvent such as chloroform and in the presence ofalcohol, with an anhydrous mineral acid, such as hydrochloric acid. Thereduced temperatures should be maintained throughout the period ofaddition of the acid. The reaction mixture can then be washed withsuccessive portions of dilute alkali and water and evaporated underreduced pressure to obtain the a-epimer.

GROUP G The novel 6u-flll01'0 and 6/8-fluoro steroid compounds of Group(G) of this invention, 2a-methyl-6,21-difluoro- 9a-halo 11 oxygenated17a hydroxy-4-pregnene-3,20- diones and the corresponding l-dehydrocompounds, for

5 3,20 dione, and 2-me'thy'1-6,21-difluoro-9a-halo--l7a-hydroxy-1,4-pregnadiene-3,11,20-trione are represented by the followingformula: t

wherein X and Y" have the meanings previously given and the 1,2-carbonatom linkage is selected from the link-' 25 ages consisting of singlebond and double bond linkages.

The novel compounds of Group (G) of this invention can be prepared inaccordance withthe follovn'ng reactions:

wherein R and Y" have the meanings previously given. The procms of Group(G) of the present invention comprises treating2ot-IHBthYl-6-fl1l0lO-9oc-h8l0-115,170:-21-trihydroxy-4-pregnene-3,20-dione 21-alkyl or aryl sulfonate (XLVIH)with a fluorinating agent to obtain the corresponding 20:methyl-6,2l-difluoro-9ashalo-1113,17- dihydroxy -4-pregnene-3,20-dione(XLIX). If desired, the 6,21-difluoro product above can be oxidized togive the corresponding2umethyl-6,21-difluoro-9a-halo-17ahydroxy-4-pregnene-3,l1,20-trione (L).Alternatively, 2a methyl-6-fluoro-9a-halo-11,8,17a-dihydroxy-21-iodo-4-pregnene-3,20-dione can be fluorinated to yield the 21- fluoro steroid(XLIX). Similarly, when the corresponding ll-keto compounds(2a-mBIhYI-G-flHOIOQa-hllm17oz, 2l-dihydroxy-4-pregnene-3,11,20-trione21-alkyl or aryl sulfonate or2wmethyl-6-fluoro-9a-halo-l7a-hydroxy-2liodo-4-pregnene-3,11,20-trione)are utilized as the starting material in the above series of reactions,Zea-methyl- 6,21-difluoro-9a-halo 17oz hydroxy-4-pregnene-3,l1,20-trione (L) is produced directly without the step of oxidation of thellfi-hydroxyl group.

The selected 2a-methyl-6,21-difluoro-9a-halo-115,170;-dihydroxy-4-pregnene-3,20-dione or 2a-methyl-6,21-difluoro 9a-halol7a-hydroxy-4-pregnene-3,11,20-trione thus produced, is l-dehydrogenatedby fermentative or chemical dehydrogenation to produce the correspondingZ-methyl 6,21-difluoro 9a-halo-l1p,l7a-dihydroxy-1,4-pregnadiene-3,20-dione (LI), or the corresponding 2- methyl6,21-difiuoro 9a-halo l7a-hydroxy-1,4-pregnadiene-3,1 1,20-trione (LII).

The starting materials for Group (G) of the present invention are the21-alkyl or aryl sulfonates of Zea-methyl- 6-fil10I0-9a-h810-1l-oxygenated-l7a-hydroxy 4pregnene- 3,20-diones (XLVIII) or the2a-methyl-6-fiuoro-9a-haloll-oxygenated 17a-hydroxy2l-iodo-4-pregnene-3,20- diones (LIII), for example,2a-methy1-6u-fluoro-9a-halo- 11,3,17a-dihYdI'0XY 4-pregnene 3,20-dioneZI-methanesulfonate, 2oz methyl 6/3-fluoro 9a-halo-ll 8,l7m-dihydroxy 4pregnene-3,20-dione 21-methanesulfonate,2amethyl-6u-fluoro-9a-halo-l7a-hydroxy-4-pregnene 3,11, ZO-trioneZI-methanesulfonate,2a-methyl-6fi-fluoro-9ahalo-l7a-hydroxy-4-pregnene-3,11,20-trione21-methanesulfonate, Zea-methyl 6a-fll10l'0 9a-halo-11p,17u-dihydroxy 21iodo 4-pregnene-3,20-dione,2a-methyl-6flfluoro-9a-halo-l1fl,17a-dihydroxy-21-iodo 4 pregnene-3,20-dione,2a-methyl-6u-fluoro-9a-halo-l7a-thydroxy-2liodo-4pregnene-3,11,20-trioneand 2a-methyl-6/3-fluoro 9oz halo17a-hydroxy-21-iodo-4-pregnene-3,11,20-trione prepared in Group (F),above, and represented in Group (F) by Formulae XLI and XLII.

In carrying out the process of the present invention, the selected2a-methyl-6-fluoro-9a-halo-11B,17a,21-trihydroxy-4-pregnene-3,20-dione21-alkyl or aryl sulfonate (XLVIH) is reacted with a fluorinating agentsuch as potassium fluoride, silver fluoride or antimony fluoride in aninert solvent such as dimethyl sulfoxide, acetonitrile,dimethylformamide or ethylene glycol solution, the preferred combinationbeing potassium fluoride in dimethylsulfoxide... The reaction isadvantageously conducted under continuous heating, and it proceedsgenerally for a period of about six to 24 hours, fifteen to twenty hoursusually being sufficient. The reaction mixture is then diluted withwater and extracted with an organic solvent such as methylene chloride,chloroform, benzene, and the like, and purified in a conventionalmanner, as, for example, by chromatography or recrystallization to givethe corresponding 2oc-Il16thyl-6,21-diflllOI'O-9u-h3l0 115,17-dihydroxy-4-pregnene-3,ZO-dione.

Alternatively, the selected 2u-methyl-6-fluoro-9m-halo- 1118,1711dihydroxy-Zl-iodo-4-pregnene 3,20-dione, dissolved in a solvent such asacetonitrile, dimethylformamide or ethylene glycol, is treated with ametal fluoride such as silver fluoride, antimony fluoride, potassiumfluoride, or the like, acetonitrile and silver fluoride being preferred.The metal fluoride should be added in small 28 quantities at intervals,and the reaction mixture should be protected from light during thereaction period, which usually ranges from about one-half to six hours.The reaction mixture is then concentrated and the product extracted asin previous purification steps to yield the corresponding 211methyl-6,2l-difluoro-9a-halo-115,17a-dihydroxy-4-pregnene-3,20-dione.

The foregoing reactions constituting either the principal or alternativeroutes can likewise be conducted on the corresponding ll-keto compounds.

The oxidation of the selected 2u-methyl-6,2l-difluoro-9a-halo-11p,17a-dihydroxy-4 pregnene-3,20-dione can be carried out by avariety of methods, such as, for example, by oxidizing the said6,21-difluoro steroid in acetic acid solution with chromium trioxide,using molar quantities or a slight excess, such as from ten to thirtypercent excess, or by oxidizing with a haloamide or imide of an acid,such as N-bromoacetamide, N-chlorosuccinimide, or N-bromosuccinimidedissolved in pyridine, dioxane, or other suitable solvents. At theconclusion of the desired oxidation reaction, the excess oxidant isgenerally destroyed by addition of methyl alcohol, ethyl alcohol, andthe like for the chromic acid oxidant or a bisulfite forN-bromoacetamide, N-bromosuccinimide and other N-haloacyl amides andimides. Thereafter, the resulting2u-methyl-6,21-difluoro-9a-halo-17a-hydroxy-4- pregnene-3,11,20-trioneis recovered by conventional means, such as by extraction withwater-immiscible solvents, e.g., methylene chloride, ether, benzene,toluene or the like.

The dehydrogenation of the selected 2a-methyl-6,21-difluoro ahalo-1l-oxygenated-17a-hydroxy-4-pregnene- 3,20-dione, for example2a-methyl-6,2l-difluoro-9a-halo- 1118,17a-hydroxy-4-pregnene-3,20dione(XLIX) or 2onmethyl 6,21 difluoro-9a-halo-l7a-hydroxy-4-pregnene-3,11,20-trione (L) to obtain the corresponding l-dehydro compounds, forexample, 2-methyl-6,21-difiuoro-9a-halo-1lfl,17a-dihydroxy-1,4-pregnadiene-3,20-dione (LI) and 2methyl-6,21'difluoro9a-ha1o-17a-hydroxy-l,4-pregnadiene-3,ll,20-trione(LII) can be carried out by fermentative or chemical dehydrogenation.Microorganisms such as, for example, Septomyxa, Corynebacterium,Didymella, Calonectria, Alternaria, Colletotrichum, Cylindrocarpon,Ophiobolus, Fusarium, Listeria, Erysipe lothrix, Mycobacterium,Tricothecium, I/eptosphaeria, Cucurbitaria, Nocardia, and enzymes offungi of the family Tuberculariaceae can be used under fermentationconditions well known in the art (e.g., US. 2,602,769) and furthermoreillustrated by Examples 7G and 8G herein.

When Septomyxa is used to eflect the dehydrogenation of the compounds ofFormula XLIX it is advantageous to use with the substrate and medium asteroid promotor, such as, progesterone, 3-ketobisnor-4-cholen-22-al, 3-ketobisnorcholenic acid, 11ft,21-dihydroxy-1,4-l7(20)-pregnatrien-S-one, and the like.

The chemical dehydrogenation can be carried out with selenium dioxideaccording to known procedures [e.g., Meystre et al., Helv. Chim. Acta,39, 734 (1956)].

Alternatively, if desired, fluorination at carbon atom 21 can beaccomplished first and this can then be followed by halogenation atcarbon atom 9.

For example, 20:methyl-6,21-difluoro1lfi-l7m-dihydroxy-4-pregnene-3,20-dione prepared inGroup (E) above can be dehydrated with N-brornoacetamide and anhydroussulfur dioxide in pyridine solution by permitting the reaction tocontinue until a negative acidified potassium iodide-starch test of thereaction mixture is obtained. Dilution with cold water results in theprecipitation of 2a-methyl-6,2l-difluoro-l7a-hydroxy-4,9(11)-pregnadiene-3,20-dione, which can be purified by recrystallization fromacetone. The crystalline product can then be reacted in methylenechloride-tertiary-butyl alcohol solution with perchloric acid andN-bromoacetamide or N-iodosuccinimide to produce a reaction mixture from29 which 20:methyl-6,2l-difiuoro-9ot-bromo-115,17a-dihydroxy-4-pregnene-3,20-dioneor the corresponding 6,21- difluoro-Qa-iodo compound can be recovered byprecipitation with ice water and recrystallization from acetone. Thelatter steroids can then be reacted in acetone solution with anhydrouspotassium acetate at reflux temperatures to produce2a-methyl-6,2l-difluoro-9;3,l1[3-oxidol7a-hydroxy-4-pregnene-3,ZO-dione,which is recoverable from the reaction mixture by chromatography and canbe further purified by recrystallization from Skellysolve Bhexanes-actone. Reaction of the said 9,11-oxido compound in methylenechloride solution with aqueous hydorgen fluoride or liquid hydrogenfluoride in the presence of tetrahydrofuran is productive of 2u-methyl-6,9a,21 trifiuoro-11p,17u-dihydroxy-4 pregnene-3,20-dione. Substitutionof aqueous hydrogen chloride for the hydrogen fluoride above yields2a-methyl-6,21-difluoro- 9d-chloro '1 118,170:dihydroxy-4-pregene-3,20-dione. If

desired, either the 9oc-fl11010, 9u-chlor, 9u-bromo or 9miodo productcan be oxidized, for example, with chromic acid to give20t-methy1-6,906,21-tl'lflll0l'O-170t-hYdI'OXY-4-pregnene-3,11,20-trione or the corresponding 9a-chloro, 9a-br0mo or9a-i0d0 compounds.

In like manner, substitution of 2-methyl-6,21-difluoro- 1118,1711dihydroxy 1,4 pregnadiene 3,20 dione prepared in Group (E), above, for2u-methyl-6,2l-difluoro- 1118,17b dihydroxy 4 -.pregnene 3,20 dione inthe above alternative process is productive ofthe corresponding 2 methyl6,21 ditluoro 9a halo '11 oxygenated 17a hydroxy 1,4 pregnadiene 3,20diones, for example 2 methyl 6,9a,21 trifluoro 1113,17ot- 'dihydroxy 1,4pregnadiene 3,20 dione, 2 methyl- 6,'9a,21 trifluoro 17a hydroxy 1,4pregnadiene- 3,11,20-trione and their corresponding 9a-chloro, 9a--bromo and 9a-iodo analogues. 1

In the foregoing processes, it should be understood that thecorresponding 6,8-epimer can be utilized at any stage and the 6ot-epimerobtained at appropriate intermediate stages by treatment of the6B-co'mpound, at temperatures of-zero degrees centigrade or slightlylower, in an organic solvent such as chloroform and in the presence ofalcohol, with an anhydrous mineral acid, such as hydrochloric acid. Suchtemperatures should be maintained throughoutthe period of addition ofthe acid. The reaction mixture-can then be washed with successiveportions of dilute alkali and water and evaporated under reducedpressure to obtain the 6u-epimer.

The following preparation and examples are illustrative ofthe processand products of the present invention but are not to be construed aslimiting.

In the examples which follow, the Roman numeral ollowing the name of acompound is used to indicate he relation-of the compound to the reactionschemes deicted and described above.

PREPARATION 1 2u-methyl-6ot-flu0ro-1 1 8,1 7a,21 -trihydrxy-4-pregnene-3,20-dione Zwmethyl 6m fluoro 11,8,17oc,21 trihydroxy 4-pregnene-3,20-dione, ZI-acetate, 278 milligrams (0.637 millimole) wasdissolved in 30 milliliters of methyl alcohol. This solution was purgedof air by bubbling nitrogen through the solution for five minutes. Asolution of 150 milligrams of potassium bicarbonate in 3 milliliters ofwater was also purged of air with nitrogen and was then added to thesolution of the steroid. This reaction mixture was stirred at roomtemperature and kept in a nitrogen atmosphere for five hours. Thereaction mixture was made barely acid by the addition of two drops ofglacial acetic acid and was diluted with thirty milliliters of water.The methanol was removed by distillation at reduced pressure. Theproduct was extracted fiorri the aqueous mixture with threeten-milliliter portions of methylene chloride. The extract was driedover anhydrous'sodium sulfate and evaporated to dryness to give 2amethyl 6p -fluoro 17a,21 dihydroxy' 4- pregnene-3,11,20-trione21-acetone is productive ot the corresponding 21-hydroxy compounds,2a-methyl-6a-fluoro- 1711,21 dihydroxy 4 pregnene 3,11,20trione,2umethyl 6,6 fluoro 1l/3,l7oz,21 trihydroxy 4--,preg nene 3,20dione and 20a -methyl --6}8 -.fiuoro-17u,2-1-dihydroxy-4-pregnene-3,l1,20-trione.

EXAMPLE 1A Five -milliliter portions of a medium, in 250-milliliterErlenmeyer flasks, containing one percent glucose, two percentcorn-steep liquor (sixty percentsolids') and tap*water, are adjusted toa pH of 4.9. This mediumis sterilized for'45 minutes at fifteen, poundsper square-inch pressure and inoculated with a one to two day vegetativegrowth of 'Septomyxa ajfinis A.T.CJC. 6737. I'I'he Erlen" .meyer flasksare shaken at room temperature (about.26

to 28 degrees centigrade) for a pen'odwof three days. At the end of thisperiod this SOD-milliliter volume is used as an inoculum for ten liters.of-the same glucose-corn steep liquor medium which in addition contains'fivemilliliters of an antifoam compound (a mixture of lard oil andoctadecanol). flhe fermentor is placed "into the water- 'bath, adjustedto 28 degrees centigradeand 'the contents stirred thoroughly (300r.p.m.) and -aerated(0.'l'literof air per minute to ten liters of beer).

\After twenty hours of incubation, when a good growth has beendeveloped, one gram of 2w-methyl-6a-fluoro-11 3;17a,21-trihydroxy-4-pregnene-3,20-dione (III) plus lone-half gram of 3-ketobisnor-4-cholen-22-al dissolved in sixteen milliliters ofdimethylformamide is added and the incubation carried out at the sametemperature (28 degrees centigrade) and aerationfor a period of 72 hours(final pH- 8z3). The mycelium is filtered oif and extracted with-threeZOO-milliliter portionsof acetone. The beer is extracted with threeoneliter portions of methylene chlorideandthereupon the acetoneextractsand the extracts of the beer-are combined, dried over anhydroussodium sulfate andevaporated. The resulting residue is purified bychromatography over a Florisil anhydrous magnesium silicate column andrecrystallized from' acetone-Skellysolve. B hexanes to give2-methy1-6wfluoro-11B,17a,21-trihydroxy- 1,4-pregnadiene-3,20-dione, acrystalline solid,

Instead of Septomyxa, species of other genera such as Corynebacterium,Didymella, Calonectria, Alternaria, Colletotrichurn, Cylindnocarpon,Ophiobolus, J Fusarium, Listeria, vErysipelothrix, Mycobacterium,Tricothecium, Leptosphaeria, Cucurbitaria, Nocardia, andenzymes of fungiof the family Tuberculariaceae can be used to introduce a A -bond into2a-methyl-6wfluoro l1fl,17a,21-tri hydr0xy-4-pregnene-3,20-dione.

EXAMPLE 2A 2 methyl-6a-flu0ro-17a,21-dihy dr0xy#1,4 pregnadiene-3,11,20-tri0ne (IV) Five 100-milliliterportions of a medium, in250-milliliter Erlenmeyer flasks, containing one percent glucose, twopercent corn steep liquor (sixty percent solids) and tap water, areadjusted to a pH of 4.9. This medium is sterilized (for 45 minutes atfifteen pounds per square inch pressure and inoculated with a one to twoday vegetative growth of Septomyxa afiinis A.T.C.C. 6737. The Erlenmeyerflasks are shaken at room temperature (about 26 to 28 degreescentigrade) for a period of three days. At the end of this period thisSOO-milliliter volume used as an inoculum for ten liters of the sameglucosecorn steep liquor medium which in addition contains fivemilliliters of an antifoam compound (a mixture of lard oil andoctadecanol). The fermentor is placed into the water-bath, adjusted to28 degrees centigrade and the contents stirred thoroughly (300 r.p.m.)and aerated (0.1 liter of air per minute to ten liters of beer). Aftertwenty hours of incubation, when a good growth has been developed, onegram of 2a-methyl-6u-fiuoro-170;,21- dihydroxy-4-pregnene-3,11,20-trione(III) plus One half gram of 3-ketobisnor-4-cholen-22-al dissolved insixteen milliliters of dimethylformamide is added and the incubationcarried out at the same temperature (28 degrees centigrade) and aerationfor a period of 72 hours (final pH 8.3). The mycelium is filtered offand extracted with three ZOO-milliliter portions of acetone. The beer isextracted with three one-liter portions of methylene chloride andthereupon the acetone extracts and the extracts of the beer arecombined, dried over anhydrous sodium sulfate and evaporated. Theresulting residue is purified by chromatography over a Florisilanhydrous magnesium silicate column and recrystallized fromacetone-Skellysolve B hexanes to give2-methyl-6a-fluoro-17a,2l-dihydroxy-lA-pregnadiene-ll1,20-trione, acrystalline solid.

Instead of Septomyxa, species of other genera such as those listed inExample 1A can be used to introduce a A -bond into2a-methyl-6-fluoro-17a,21-dihydroxy-4-pregnene-3,1 1,20-trione.

ExAMPLE 3A2-methyl-6fl-fluoro-113,17:1,21-trihydroxy-1,4-pregnadiene-3,20-dine(IV) A stoichiometric equivalent amount of Za-methyI-GB- fluoro11,8,17a,21 trihydroxy-4-pregnene-3,20-dione is substituted for 2amethyl-6a-fluoro-11,8,l7a,21 trihydroxy-4-pregnene-3,20-dione in theprocedure of Example 1A, to obtain 2-methyl-68-fiouro-11fl,l7a,21-trihydroxy-l,4-pregnadiene-3,20-dione, acrystalline solid.

EXAMPLE 4A 2 methyl-6fl-fluora-17a21 -dihydroxy-1,4-pregnadiene-3,11,20-tri0ne (IV) A stoichiometric equivalent amount of2a-methyl-6pfiuoro-17a,21-dihydroxy-4-pregnene-3,11,20-trione issubstituted for2u,methyl-6a-fiuoro-17a,2l-dihydroxy-4-pregnene-3,1l,20-trione in theprocedure of Example 2A, to obtain 2methyl-6p-fluoro-Hull-dihydroxy-1,4-pregnadiene-3,ll,20-trione, acrystalline solid.

EXAMPLE A 2-methyl-6a- VOID-115,1 7a,21-trihydr0xy-1,4-pregnadiene-3,20-dione 21 -acetate (V) A solution is preparedcontaining fifty milligrams of 2 methyl-6a-fluoro-l1,6,17a,21-trihydroxy1,4 pregnadiene-3,20-dione (IV) in one milliliter of pyridine and onemilliliter of acetic anhydride. The solution is allowed to stand at roomtemperature for a period of 21 hours and is thereupon poured into icewater to give crystals of 2-methyl-6u-ffuoro-l1p,17m,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate, which can be purified byrecrystallization from acetone-Skellysolve B hexanes.

In the same manner, substitution of 2-methyl-6p-fiuoro- 11fi,17ot,21-trihydroxy-1,4-pregnadiene-3,20dione for 2-methyl-6a-fiuoro-1lB,l7a,2.1-trihydroxy-1,4 pregnadiene- 3,20-dioneproduces2-methyl-6fl-fluoro-11/3,17a,21-trihydroxy-l,4pregnadiene-3,20-dioneZI-acetate, a crystalline solid.

EXAMPLE 6A 2-m8thyl-6u-flu0r0-1 70:,2] dihydroxy-1,4-pregnadiene-3,11,20-trione 21 -acetate (V) A solution is prepared containing fiftymilligrams of 2 methyl 6u-fluoro-17a,2l-dihydroxy-l,4-pregnadiene-3,11,20-trione (IV) in one milliliter of pyridine and one milliliter ofacetic anhydride. The solution is allowed to stand at room temperaturefor a period of 21 hours and is thereupon poured into ice water to givecrystals of 2 methyl 6a-fluoro-17a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acetate, which can be purified by recrystallizationfrom acetone-Skellysolve B hexanes.

In the same manner substitution of 2methyl-6,B-fluoro-17a,21-dihydroxy-1,4pregnadiene-3,11,20-trione for 2- methyl 60cfiuoro-l7a,2l-dihydroxy-l,4-pregnadiene- 3,11,20-trione produces2-methyl-6/3-fluoro-17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione21-acetate, a crystalline solid.

EXAMPLE 7A 2-methyl-6u-flu0r0-11,3,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21 -hemisuccinate (V) A solution is preparedcontaining 0.5 gram of succinic anhydride and 0.1 gram of2-methyl-6a-fiuoro'l15,1711, 21-trihydroxy-1,4-pregnadiene-3,20-dione(IV) in five milliliters of pyridine. This solution is allowed to standfor a period of twenty hours, diluted with water and the mixturerefrigerated and filtered. The precipitate thus collected on filterpaper is recrystallized two times from methanol to give2-methyl-6a-fluoro-l1fl,17a,2l-trihydroxy-l,4-pregnadiene-3,20-dioneZI-hemisuccinate, a crystalline solid.

Similarly, substitution of 2-methyl-6/3-fiuoro-l15,1711,21-trihydroxy-1,4pregnadiene-3,20-dione for 2-methyl- -60: fluoro11p,1711,21-t1ihydroxy-1,4-pregnadiene-3,20- dione produces2-methyl-6fl-fiuoro-l lp,17a,21trihydroxy- 1,4-pregnadiene-3,20-dione2l-hemisuccinate, a crystalline solid.

In the same manner as in Example 7A, other esters of 2 methyl 60a fluoro11B,17u,21trihydroxy-1,4-pregnadiene-3,20-dione and2-methyl-6fi-fluoro11p,l7a,21- trihydroxy-l,4-pregnadiene-3,20-dione areprepared by allowing these compounds to react with the selected organiccarboxylic acid, preferably a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive, or the anhydride or acylhalide thereof, such as, for example, those listed, above. Illustrativeof the compounds thus produced are the 21-propionate, 21-is0- butyrate,21-(fi-cyclopentylproprionate), 21-benzoate, 21- acrylate, 21-cinnamate,21-ma1eate, and the like, of 2' methyl 60c fiuoro 11}3,17oc,21trihydroxy 1,4-pregnadiene-3,20-dione, and2-methyl-6fi-fluoro-11B,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione,represented by Formula V.

If the corresponding acylating agent is solid an inert solvent such astoluene, xylene, or dioxane can be added to effect solution and toprovide a liquid esterification medium.

If the esterifying agent is the free acid, the reaction is carried outin the presence of an esterification catalyst.

EXAMPLE 8A Z-methyl 6a flu0r0-17a,21-dihydroxy-I,4-pregnadiene-3,11,20-tri0ne ZI-hemisuccinate (V) A solution is prepared containing0.5 gram of succinic anhydride and 0.1 gram of2-methyl-6a-fiuoro-l7a,2l-dihydroxy 1,4 pregnadiene 3,11,20-trione (IV)in five milliliters of pyridine. This solution is allowed to stand for aperiod of twenty hours, diluted with water and the mixture refrigeratedand filtered. The precipitate thus collected on filter paper isrecrystallized two times from methanol to give 2-methyl-6a-fiuoro-17a,2ldihydroxy- 1,4-pregnadiene 3,11,20-trione 21-hemisuccinate, acrystalline solid.

Similarly, substitution of 2-methyl-6B-fluoro-17a,2l-dihydroxy 1,4pregnadiene 3,11,20-trione for 2-methyl- 6 x-fluoro 17oc,21 dihydroxy1,4-pregnadiene-3,1l,20- trione produces Z-methyl 6B fluoroHull-dihydroxy- 1,4-pregnadiene 3,11,20 trione 21 hemisuccinate, acrystalline solid. I

In the same manner as in Example 7A, other ester of 2 methyl 6efluoro-Hall-dihydroxy-1,4-pregnadiene-3,11,20-trione and 2 methyl-63-fluoro-17,2l-dihydroxy 1,4 pregnadiene 3,11,20-trione are prepared byallowing these steroids to react with the selected organic carboxylicacid, preferably a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive, or the anhydride or acyl halide,thereof, such as for example, those listed, above. Illustrative of thecompounds thus produced are the 21-propionate, 21-isobutyrate, 21-(6-cyclopentylpropionate), 21-benzoate, ZI-acrylate, 21-cinnamate,2l-maleate, and the like, of 2-methyl-6ufluoro- 1711,21 dihydroxy1,4-pregnadiene 3,11,20-trione and 2 methyl 65fluoro-17a,2l-dihydroxy-1,4-pregnadiene- 3,11,20-trione, represented byFormula V.

If the corresponding acylating agent is solid an inert solvent such astoluene, xylene, or dioxane can be added to effect solution and toprovide a liquid esterification medium.

If the esterifying agent is the free acid, the reaction is carried outin the presence of an esterification catalyst EXAMPLE 9A Z-methyl 6mfluoro-l13,17a,21-trihydrxy-1,4-pregnadime-3,20 dione ZI-hemisuccinatesodium salt Sodium hydroxide solution (0.1 normal) is slowly added to astirred solution of 100 milligrams of 2-methyl-6ocfluoro 11,8,17a,21trihydroxy 1,4-pregnadiene-3,20- dione 21-hemisuccinate dissolved in twomilliliters of acetone, until the pH rises to about 7.4. During theaddition of sodium hydroxide solution, five milliliters of water is alsoadded. The solution is then concentrated at 25 degrees centigrade undervacuum to remove the acetone. The resulting aqueous solution of2-methyl-6a-fluoro-11p, 17u,21 trihydroxy 1,4 pregnadiene 3,20-dione 21-hemisuccinate sodium salt is filtered and freeze-dried to give pureZ-methyl 6oz fiuoro-l1p,17a,21-trihydroxy- 1,4-pregnadiene-3,20 dione 21hemisuccinate sodium salt.

Similarly, substitution of 2-methyl-6u-fluoro-17a,21-dihydroxy 1,4pregnadiene 3,11,20-trione 21-hemisuccinate, 2 methyl 6B fluoro11/8,17rx,21 trihydroxy- 1,4 pregnadiene 3,20 dione 21-hemisuccinate,and 2-methyl-6fi-fiuoro 17a,21 dihydroxy 1,4-pregnadiene- 3,11,20 trione21 hemisuccinate for 2-methyl-6u-fluoro- 1lfl,171x,21 trihydroxy1,4-pregnadiene 3,20-dione 21- hemisuccinate produces2-methyl-6a-fluoro-17a,21-dihy droxy-l,4-pregnadiene-3,11,20-trioneZI-hemisuccinate sodium salt, 2-methyl-6B-fluoro-1 1 ,B, 17a,21-trihydroxy-1 ,4- pregnadiene-3,20-dione ZI-hemisuccinate sodiumsalt, and 2-methyl-6B-fluoro-170:,21-dihydroxy-1,4-pregnadiene 3,11,20-trione 21-hemisuccinate sodium salt, respectively.

EXAMPLE 10A' Isomerization of Z-methyl 6/3flu0r0-11,B,17oc,21-trihydroxy 1,4 pregnadiene-3,2-0-dione to2-methyl-6afluoro 11fl,17u,21 trihydroxy-I,4-pregnadiene-3,20- dione Asolution of 0.150 gram of 2-methyl-6fi-fluoro-l1fi, 17 0:,21 trihydroxy1,4-pregnadiene-3,20-dione in twelve milliliters of chloroform and 0.1milliliter of absolute alcohol is cooled to minus ten degrees centigradein an ice-salt bath and a stream of anhydrous hydrogen chloride isgently bubbled through the solution for about 2.5 hours while thetemperature is maintained between approximately minus five and minusfifteen degrees centigrade. The solution is then washed with dilutesodium bicarbonate and water, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure. Crystallization of theresidue from acetone-Skellysolve B hexanes gives 2-methy1-6a-fluoro11,B,17a,21-trihydroxy- 1,4 pregnadiene-3,20-dione, a crystalline solid.

In a similar manner 2-methyl-6/3-fluoro-17a,2l-dihy-- droxy 1,4pregnadiene 3,11,20 trione, the 21-acylates of 2 methyl 6Bfluoro-l1,8,17a,21-trihydroxy 1,4- pregnadiene-'3,20-dione, and the21-acylates of 2-methyl- 6,8 fluoro 17a,21-dihydroxy-l,4pregnadiene-3,11,20-

34 trione are converted to the corresponding 6a-fluoro conipounds.

EXAMPLE 1B 20: methyl 60: fluoro-I7a,21-dihydr0xy-4,9(1I)pregnadiene-3,20-di0ne 21 -acetate (VIII) To a solution of one gram of2u-methyl-6wfluoro-11fl, 17a,21-trihydroxy 4 pregnene-3,20-dione2l-acetate (VII) in ten milliliters of pyridine is added 0.4 gram ofN-bromoacetamide. The mixture is allowed to stand under nitrogen for aperiod of about twenty minutes, at which time it is cooled to fivedegrees centigrade. While stirring, anhydrous sulfur dioxide is passedover the sur- EXAMPLE 2B 2oz methyl 6a fluoro 9oz bromo 1lp,17u,21trihydroxy-4-pregnene-3,ZO-dione 21 -acetate (IX) To a solution of 420milligrams of 2a-methyl-6ufluoro- 1712,21 dihydroxy 4,9(11) pregnadiene3,20 dione 21-acetate (VIII) in 6.5 milliliters of methylene chloride isadded 12.5 milliliters of tertiary butyl alcohol, a solution of 1.0milliliter of 72 percent perchloric acid in 7.5 milliliters of water,and a solution of 182 milligrams of N-bromoacetamide in 3.2 millilitersof tertiary butyl alcohol. After stirring for a period of about fifteenminutes, a solution of 182 milligrams of sodium sulfite in tenmilliliters of Water is added and the mixture concentrated under reducedpressure at about sixty degrees centigrade until crystallization occurs.:After cooling in an ice bath, thirty milliliters of water is added withstirring. The crystalline product is filtered, washed with water anddried, giving essentially pure 2amethyl-6a-fluoro-9abromo 11fl,17a,21trihydroxy- 4 pregnene 3,20- dione 21-acetate. The product was used inthe succeeding example without further purification.

Substitution of another N-haloamide or an N-haloimide such asN-iodosuccinimide or N-chlorosuccinimide for the N-bromoacetamide in theforegoing reaction is productive of the corresponding 9a-halo product.

EXAMPLE 3B 2oz methyl 60c fluoro 95,113 oxido ;,21dihydroxy4-pregnene-3,20-di0ne 21 -acetate (X) A mixture of 2.816 gramsof 2a-methyl-6a-fiuoro-9abromo 11 8,17a,21 trihydroxy 4 pregnene 3,20-dione 21-acetate (IX), from Example 2B, 2.816 grams of potassiumacetate, and ninety milliliters of acetone is stirred and heated atreflux temperature for a period of approximately eighteen hours. Thereaction mixture is then concentrated to about one-half the originalvolume and cooled in an ice bath. Addition of 250 milliliters of watergives 2u-methyl-6a-fiuoro-9fi,l1B-oxido-l7a,2ldihydroxy-4-pregnene-3,20dione 21-acetate, a crystalline solid, which can be further purified byrecrystallization from acetone.

EXAMPLE 4B 2a methyl 611,911 difluoro 11fi,17a,21 trihydroxy-4-pregnene-3,20-dione 21 -acetate (XI) To 3.41 grams of liquid hydrogenfluoride cooled in a Dry-Ice bath is added, portion-wise, a slurry of1.875

droxy-4-pregnene-3,20-d-ione ZI-acetate (X) in 5.97 grams oftetrahydrofuran (distilled over sodium hydroxide) and twenty millilitersof methylene chloride which has similarly been cooled in a dry-icebath.- The steroid is dissolved completely. After standing at zero tofive degrees centigrade for a period of about seventeen hours, thereaction mixture is poured slowly into a stirred mixture of 300milliliters ice-water, fifty milliliters of methylene chloride, andtwenty grams of sodium bicarbonate. The mixture is stirred for a fewminutes, the methylene chloride layer is separated and the water phaseextracted with two fifty-milliliter portions of methylene chloride. Thecombined methylene chloride solutions are washed with water, dried andthe solvent evaporated to give an oil. The oil is dissolved in a mixtureof ten milliliters of acetic anhydride in ten milliliters of pyridineand allowed to stand for approximately twenty hours. The acetylationmixture is then poured into ice-water and extracted with methylenechloride. The extract is washed with dilute acid, dilute base and water,dried and chromatographed over a synthetic magnesium silicate column.Elution of the column with acetone in Skellysolve B hexanes gives acrystalline product, which is recrystallized several times fromacetone-Skellysolve B hexanes to give 20: methyl 60;,911 difluoro11B,l7oz,2l trihydroxy- 4-pregnene-3,20-dione 2l-acetate, a crystallinesolid.

Substitution of aqueous hydrogen chloride or hydrogen bromide for thehydrogen fluoride above is productive of the corresponding 9a-ChlOI'O or9oc-b10m0 porduct, respectively.

Substitition in the procedure of Example 1B of other 21-esters of2a-methyl-6a-fluoro and 2a-methyl-6fi-fiuorollfi,l7a,2l trihydroxy 4pregnene 3,20 diones, followed by the procedure of Examples 2B through4B, is productive of the corresponding 21-esters of Zea-methyl- 6,90:difluoro 1-lfi,17a,21 trihydroxy 4 pregnene- 3,20 dione, 2oz methyl 6fluoro 90c chloro 11B, 17a,2l trihydroxy 4 pregnene 3,20 dione, and2amethyl 6 fluoro 9oz bromo 11,9,17a,2ltrihydroxy-4-pregnene-3,20-dione, wherein the 6-fluoro substituent isthe 611- or 6,8-epimer.

EXAMPLE 5B 2a-methyl-6a,9a-difluoro-1113,17a,21-trihydroxy-4-pregnene-3,20-dione (XII) Nitrogen is bubbled through a solution of0.33 gram of 2a methyl 6u,9a difluoro llfi,l7a,2ltrihydroxy-4-pregnene-3,20-dione 21-acetate (XI) in 33 milliliters ofmethanol for a period of about fifteen minutes. To this is added asolution of 0.33 gram of potassium bicarbonate in four milliliters ofwater, likewise treated with nitrogen. After stirring under nitrogen fora period of approximately five hours, the base is neutralized by theaddition of 2.5 milliliters of five percent hydrochloric acid. Themixture is then concentrated under reduced pressure at about fiftydegrees centigrade to about five milliliters. The residue is taken up inethyl acetate, washed, dried and evaporated to dryness. Crystallizationfrom acetone-Skellysolve B hexanes yields 2a-methyl-6a, 9oz difluorol1]3,17a,2l trihydroxy 4 pregnene 3, 20-dione (XI-I), a crystallinesolid.

Substitution of the corresponding Qua-chloro or 90cbromo 2a methyl 6ozfluoro 11B,17a,21-trihydroxy-4-pregnene-3,20 dione ZI-acetate in theabove hydrolysis is productive of 2a-methyl-6ot-fluoro-9u-chloro-1lfl,17oc,2l trihydroxy 4 pregnene 3,20 dione and the corresponding9m-bromo compound.

The 2a-methyl-6a,9a-difluoro-1lB,l7a,2l-trihydroxy-4-pregnene-3,20-dione of this example or its 9ec-Chl010 or 9a-br0m0analogues can be re-esterfied at the 2l-hydroxy group with the selectedorganic carboxylic acid, preferably a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive, or the anhydrideor acyl halide thereof, such as for example, a saturated straightchainaliphatic acid, e.g. formic, acetic, propionic, butyric, valeric,hexanoic, lauric, a saturated branched-chain aliphatic acid, e.g.,trimethylacetic, isobutyric, isovaleric,

tertiary butylacetic, a cycloaliphatic saturated acid, e.g.fl-cyclopentylpropionic, cyclohexane-carboxylic, cyclohexylacetic, analkaryl acid, e.g., benzoic, pentylacetic, fi-phenylpropionic, 0-, m-,and p-toluic, a saturated dibasic acid (which can be converted intowater-soluble, e.g., sodium salts), e.g., succinic, adipic; a monobasicunsaturated acid, e.g., acrylic, crotonic, undecylenic, propiolic,undecolic, cinnamic, dibasic unsaturated acids (which can be convertedinto water soluble, e.g., sodium salts), e.g., maleic, citraconic, andthe like.

If the corresponding acylating agent is solid an inert solvent such astoluene, xylene, or dioxane can be added to eifect solution and toprovide a liquid esterification medium.

If the esterifying agent is the free acid, the reaction is carried outin the presence of an esterification catalyst, such as for example,p-toluenesulfonyl chloride, trifluoroacetic anhydride, p-toluenesulfonicacid, trifluoroacetic acid, sulfuric acid and the like.

Reaction conditions which are apt to affect the labile llfi-hydroxygroup or 6-halo group should be avoided.

The resulting 2a-rnethy1-6a,9a-dlfiuOrO-11B,17oc,21-trihydroxy-4-pregnene-3,ZO-dione 2l-acylate and its 9a-Cl1l0- ro and9a-bromo analogues can be oxidized using the procedure shown in Example7B, below, to produce the corresponding2oz-methyl-6a,9m-difiuoro-1711,2l-dihydroxy- 4-pregnene-3,l1,20-trione2l-acylate, 2a-methyl-6a-fluord9a-chloro-l701,21-dihydroxy-4-pregnene-3,11,20-trione 21- acylate, andZea-methyl-6a-fiuoro-9a-bromo-171:,2l-dihydr0xy-4-pregnene-3,l1,20-trione21 acylate, respectively.

EXAMPLE 6B To a solution of 0.5 gram of 2a-methyl-6a,9a-difiuoro-11,3,l7a,2l-trihydroxy-4-pregnene-3,20-dione (XII) and one milliliter ofpyridine in 35 milliliters of tertiary butyl alcohol is added 250milligrams of N-bromoacetamide. After standing at room temperature for aperiod of sixteen hours, the reaction mixture is diluted with 25milliliters of water containing 250 milligrams of sodium sulfite andconcentrated to about twenty milliliters, at which point precipitationoccurs. The thus-obtained precipitate is collected on a filter andrecrystallized three times from ethyl acetate and Skellysolve B hexanesto give 2m-methyl-6u; 9adifluoro-l7a,2l-dihydroxy 4pregnene-3,11,20-trione (XIII).

Substitution of the corresponding Qua-chloro and 9abromo startingmaterial in the above oxidation gives 2amethyl-6m-fiuoro-9wchloro-17a, 2l-dihydroxyl-pregnene- 3,11,20-trione and the corresponding 9a-bromocompound.

EXAMPLE 7B 2a-methyl-6a,9a-difluoro-I 7a,21 -dihydr0xy-4-pregnene-3,11,20-tri0ne 21-acetate (XIV) A solution is prepared containing 0.5gram of 2c:- methyl-6a,9a-difluoro-1lB,17a,21-trihydroxy -4- pregnene-3,20-dione Zl-acetate (XI) 0.15 gram of chromium tri' oxide, tenmilliliters of glacial acetic acid and one-half milliliter of water.This mixture is stirred and maintained at room temperature for a periodof about eight hours, after which the reaction is terminated by additionof methanol. Thereafter, the mixture is poured into fifty milliliters ofice water and the thus-obtained precipitate collected on a filter andrecrystallized three times from ethyl acetate and Skellysolve B hexanesto give Zen-methyl- 6a,9u-difiuoro-17u,21-dihydroxy 4pregnene-3,11,20-trione 21-acetate (XIV).

Substitution of the corresponding 9a-chloro and 9abromo startng steroidin the above reaction produces 20:- methyl-6a-fluoro-9a-chloro-l7a,2l-dihydroxy-4- pregnene- 3,l1,20-trione21-acetate and the corresponding 9a-bromo compound,

' 37. ExAMrLB 8B EXAMPLE 9B Substituting 2a-methyl-6fl-fluoro-118,17a,21-trihydroxy- 4-pregnene-3,20-dione 21-acetate for the startingmaterial in Example 1B and following the procedures of Examples 1Bthrough 8B, but maintaining near neutral reaction conditions, there isproduced as the final product of each example the corresponding6B-steroid, giving ultimately in Example 8B 2a-methyl-6,B,9u difluoro170:,21 dihydroxy-4-pregnene-3,11,20-trione,Za-HIBthYl-Gfl-flllOIO-9occhloro-17 a,21-dihydroxy-4-pregnene 3,11,20trione and 2rx-methyl-6fl-fluoro9a-bromo-1704,2l-dihydroxy-4pregnene-3,1 1,20-trione.

The 6fi-epimers thus obtained, as products of each of the foregoingexamples, can be converted to the corresponding 6a-epimers by treatmentwith an acid or base in an organic solvent, following the procedure ofExample 10A, herein.

EXAMPLE 1C 2-methyl-6a-flu0r0-1 711,21 -dihydroxy-I ,4,9 (11)pregnatriene-3,20-dione 21 acetate (XVII) To a solution of 1.05 gramsof 2-methyl-6a-fluoro-1lp3,17a,21-t11'hydroxy-1,4-pregnadiene-3,20-dione 21 acetate (XVI) in tenmilliliters of pyridine is added 0.517 gram of N-bromoracetamide. Themixture is allowed to stand under nitrogen for a period of about fifteenminutes, at which time it is cooled to about five degrees centigrade.While stirring, sulfur dioxide is passed over the surface until thesolution gives no color change with acidified starch-iodide paper. Thetemperature of the reaction mixture is not allowed to go above twentydegrees centigrade during the sulfur dioxide addition. The mixture isthen poured into 100 milliliters of ice-water, resulting inprecipitation of2-methyl-6a-fluoro-17a-hydroxy-21-acetoxy-1,4,9(11)-pregnat1iene-3,20-dione,a crystalline solid.

EXAMPLE 2C Z-methyl-6a-flu0r0-9a-brom0-1 .7 8,1 7u,21 -trihydroxy- 1,4-pregnadiene-3,2 O-dione 21 -acetate (XVIII) To a solution of 1.27grams of2-methyl-6oe-fluoro-l7uhydroxy-21-acetoxy-1,4,9(1l)-pregnatriene 3,20dione (XVII) in 19.5 milliliters of methylene chloride is added 38milliliters of tertiary butyl alcohol, a solution of three millilitersof 72 percent perchloric acid in 22.5 milliliters of water, and asolution of 0.55 gram of N-brornoacetamide in 9.6 milliliters oftertiary butyl alcohol. After stirring for a period of about fifteenminutes, a solution of 0.55 gram of sodium sulfite in thirty millilitersof water is added and the mixture concentrated under reduced pressure atabout sixty degrees centigrade until crystallization occurs. Aftercooling in an ice bath, 100 milliliters of water is added with stirring.On filtering the crystalline product, followed by washing with water anddrying, a yield of essentially pure 2-methyl-6u-fiuoro- 9a-b10m0 115,17dihydroxy 21 acetoxy 1,4 preg- "38' nadiene-3,20-dione is obtained. Theproduct is used the succeeding example without further purification;

Substitution of N-iodosuccinimide or N-chlorosuccinirnide for theN-bromoaicetamide in the foregoingreaction is productive of thecorresponding 9a-i0d0 or 9achloro product, respectively.

EXAMPLE 3C A mixture of 1.749 grams of 2-methyl-6d-fluoro-9a bromo1lfi,17oz,21 trihydroxy 1,4 pregnadiene 3,20- dione 21-acetate (XVIII),1.749 gramsv of potassium acetate, and fifty milliliters of acetone isstirred and heated at reflux temperature for a period of approximatelyeighteen hours. The reaction mixture is then concentrated to aboutone-half the original volume, cooled and poured into 300 milliliters ofwater to give Z-mcthyl- 6qt-fl11010-9fl;l1}3 oxido 17u,21 dihydroxy 1,4pregnadiene-3,20-dione 21-acetate, a crystalline solid, which can befurther purified by recrystallization from acetone.

EXAMPLE 4C 2-methyl-6a,9a-diflu0ro-I113,17a,21-trihydr0xy-I,4-pregnadiene-3,20-dione 21 -acetate (XX) To 5.2 grams of liquid hydrogenfluoride cooled in a dry-ice bath, there is added, portion-wise, aslurry of 2.276 grams of 2-methyl6u-fluoro-9fi,11fl-oXido-17a,21-dihydroxy-1,4-pregnadiene 3,20-dione 21-acetate (XIX) in nine grams oftetrahydrofuran (distilled over NaOH) and 28 milliliters of methylenechloride which has similarly been cooled in a dry-ice bath. Afterstanding at zero to five degrees centigrade for a period of' aboutseventeen hours, the reaction mixture is poured slowly into a stirredmixture of 500 milliliters of water and 25 grams of sodium bicarbonate.The mixture is stirred for a few minutes, and the product isextracted'with three -milliliter portions of methylene chloride. Themethylene chloride solutions are washed with water, dried, andchromatographed over synethetic [magnesium silicate. The material elutedfrom the column with acetone in Skellysolve B hexanes is recrystallizedfrom ethyl acetate-Skellysolve B hexanes giving 2-methyl-6ui,9adifluoro11B,17oc,21 trihydroxy-1-4-pregnadiene 3,20 dione ZI-acetate, acrystalline solid. I

Substitution of aqeous hydrogen chloride and hydrogen bromide for thehydrogen fluoride above is productive of the corresponding 9u-chloro andQubromo product, respectively.

Substitution in the procedure of Example 1C of other 21-esters of2-methyl-6a-fluoro-11B,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione or2-methyl-6fl-fluoro-1 1B,17a,21- trihydroxy-1,4-pregnadiene-3,20-dionefollowed by the procedures of Example 20 through 40 above, is productiveof the corresponding 21-esters of 2-methyl-6,9 a-difluoro 11,8,17a,21trihydroxy 1,4 pregnadiene 3,20- dione,2-methyl-6-fluoro-9u-chloro-11B,17ok,21-trihydroxy- 1,4-pregnadiene-3,20dione and 2-methyl- 6-fl uoro-9 abromo 11;8,17a,21trihydroxy 1,4 pregnadiene 3,20- dione, wherein the 6-fluorosubstitutent is ether in the 60: or 6B configuration.

Among the 21esters of 2-methyl-6a,9a-difluoro- 11B,17u,21 trihydroxy 1,4pregnadiene-3,20-dione, the following are of particular interest becauseof the enhanced qualities of water-solubility or prolongedpharmacological activity which they possess, such esters beingspecifically embraced within the present invention: 2 methyl 6u,9adifluoro 11,3,17u,21 trihydroxy-1,4- pregnadiene-3,20-dione2l-hemisuccinate, 2-methyl-6pa,9adifluoro 11,8,17a,21 trihydroxy 1,4pregnadiene-3,20- dione 21 hemiglutarate, 2 7 methyl 7 6a,9a difluoro 115,17 0:,21 trihydroxy 1,4 pregnadiene-3,20- dione 21-hemi-B,B-dimethylglutarate, and 2-methyl-6 a,9a-difiuo 1 o- 11,8,17a,21trihydroxy 1,4 pregnadiene-3,20-di0ne 21 39 hemimaleate, as the freeacids or as the basic salts thereof (such as the alkali metal salts, andparticularly the sodium salt), the amine salts (such as diethanolamine,epinephrine, etc.), phosphate and xanthogenate.

EXAMPLE C Nitrogen is bubbled through a solution of 1.4 grams of 2methyl 641,90: difluoro 11B,17ot,21 trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate (XX) in 140 milliliters ofmethanol for about fifteen minutes. To this is added a solution of 1.4grams of potassium bicarbonate in 17.5 milliliters of water likewisetreated with nitrogen. After stirring under nitrogen for about fivehours, the base is neutralized by the addition of 1.5 milliliters ofacetic acid in forty milliliters of water. The mixture is thenconcentrated under reduced pressure at about 55 degrees centigrade untilcrystallization starts. The slurry is then cooled'in an ice bath,diluted with 100 milliliters of water, and filtered to give2methyl-6a,9a-difluoro-11,6,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione, a crystalline solid.r

The 2 methyl 60c fluoro 9a chloro 11fi,17oz,21-trihydroxy-l,4-pregn'adiene-3,20-dione and its 9a-bromo analogue areprepared from their corresponding 21-acylates by hydrolysis in anacid-catalyzed reaction, as, for example, with methanol containinghydrochloric acid.

The 2 methyl 6a,9a difluoro l1B,17u,21trihydroxy-l,4-pregnadiene-3,20-dione of the present example and its9a-chloro and 9a-bromo analogues can be reesterified at the 21-p0sitionwith the selected organic carboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive,or the anhydride or acyl halide thereof, such as for example, asaturated straight-chain aliphatic acid, e.g., formic, acetic,propionic, butyn'c, valeric, hexanoic, lauric, a saturatedbranched-chain aliphatic acid, e.g., trimethyl acetic, isobutyric,isovaleric, tertiary butylacetic, a cycloaliphatic saturated acid, e.g.,fi-cyclopentylpropionic, cyclohexane-carboxylic, cyclohexylacetic, analliaryl acid, e.g., benzoic, phenylacetic, B-phenylpropionic, o-, m-,and p-toluic, a saturated dibasic acid (which can be converted intowater-soluble, e.g., sodium, salts), e.g., succinic, adipic; a monobasicunsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic,undecolic, cinnamic; dibasic unsaturated acids (which can be convertedinto water soluble, e.g., sodium, salts), e.g., maleic and citraconic,and the like.

If the corresponding acylating agent is solid an inert solvent such astoluene, xylene, or dioxane can be added to effect solution and toprovide a liquid esterification medium.

If the esterifying agent is the free acid, the reaction is carried outin the presence of an esterification catalyst, such as for example,p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p toluenesulfonicacid, trifluoroacetic acid, sulfuric acid and the like.

The resulting 2-methyl-6a,9a-difluoro-1lfi,17a,2l-tri- 'hydroxy 1,4pregnadiene 3,20 dione 21 acylate and its 9u-chloro and 9a-bromoanalogues can then be oxidized according to the procedure of Example GOto produce the corresponding 2l-acylates of 2-methyl-6u,9adifluoro1701,21 dihydroxy 1,4 pregnadiene 3,11,20- trione, 2 methyl 6a fluoro9oz chloro 170:,21 dihydroxy 1,4 pregnadiene 3,11,20 trione and 2-methyl 60c fluoro 9oz bromo 170:,21 dihydroxy- 1,4 pregnadiene 3,11,20trione, respectively.

Alternatively, the hydrolyzed 9a-fiuoro, 9a-chloro and 9u-bromoproducts, before re-esterification can be oxidized with an N-haloamideor N-haloimide in pyridine solution to obtain 2-methyl 60:,90: difluoro17,21- dihydroxy 1,4 pregnadiene 3,11,20 trione, 2 meth- -40 yl 6afluoro 9oz -"chloro 170:,21 dihydroxy 1,4- pregnadiene 3,11,20 trioneand 2 methyl 6a fluoro- 9a bromo 170:,21 dihydroxy 1,4 pregnadiene-3,11,20 trione.

EXAMPLE 6C Z-methyl-6a,9a-difluor0-17a,21-dihydroxy-1 ,4-pregnadiene-3,11,20-trione 21 -acetate (XXIII) A solution is preparedcontaining 0.5 gram of 2- methyl 611,911 difluoro 11fi,17cz,21trihydroxy 1,4- pregnadiene-3,20-dione 21-acetate (XX), 015 gram ofchromium trioxide, ten milliliters of glacial acetic acid and one-halfmilliliter of water. This mixture is stirred and maintained at roomtemperature for about eight hours. Thereafter, the excess oxidant isdestroyed by addition of methanol and the mixture is poured into fiftymilliliters of ice water. The resulting precipitate is collected on afilter and recrystallized three times from ethyl acetate-Skellysolve B'hexanes to give 2 methyl 60:,901; difluoro 1711,21 dihydroxy 1,4pregnadiene 3,11,20- trione 21-acetate, a crystalline solid.

Similarly, the corresponding 9a-Ch101'0 and 9a-bromo starting materialscan be oxidized to give 2 methyl 6afluoro 9a chloro 17,21 dihydroxy 1,4pregnadiene 3,11,2-0 trione 21 acetate and 2-methyl 6afluoro 9a bromo170:, 21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21 acetate,respectively EXAMPLE 7C 6fl-epimers Substituting 2 methyl 6B fluorol1/3,17u,21 trihydroxy 1,4 pregnadiene 3,20 dione 21 acetate for thestarting material in Example 1C and following the procedures of Examples1C through 6C, but maintaining near neutral reaction conditions, thereis produced as the final product of each example the corresponding6B-steroid, giving ultimately in Example 60 the 2 methyl 65,90 difluoro17:1,21 dihydroxy 1,4- pregnadiene 3,11,20 trione 21 acetate, 2 methyl-6 fluoro 9a chloro 170:,21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21acetate and 2 methyl- 63 fluoro 9oz bromo 17u,21 dihydroxy 1,4pregnadiene 3,11,20 trione 21 acetate.

The fifi-epimers thus obtained, as products of each of the foregoingexamples, can be converted to the corresponding Ge-epimers by treatmentwith an acid or base in an organic solvent, following the procedure ofExample 10A herein.

EXAMPLE 1D 2a-methyl-6u-flu0r0-1 1,9,1 701,21-trihydroxy-4-pregnene-3,20-dione 21 -methanesulfonate (XXVI) To a solution of milligrams(0.254 millimole) of crude Zea-methyl 6a fluoro 1lf3,17a,2ltrihydroxy-4- pregnene-3,20-dione (XXV) in three milliliters of pyridenepreviously cooled to zero degrees centigrade there was added 0.2milliliter of methanesulfonyl chloride. The reaction mixture was stirredat a temperature of zero to minus five degrees centigrade for a periodof two hours. The reaction mixture was diluted with water and extractedwith methylene chloride. This extract was washed with ice cold dilutehydrochloric acid to remove the pyridine. The methylene chloride extractwas then washed with cold dilute aqueous sodium bicarbonate solution anddried over anhydrous sodium sulfate. The dried extract was thenconcentrated to dryness by distillation at reduced pressure. Thesemicrystalline, buffcolored product obtained was2a-methyl-6a-fluoro-llfi, :,21-trihydroxy-4-pregnene-3,20-dioneZI-methanesulfonate.

1. 2A - METHYL - 6A - FLUORO - 11B,17A - DIHYDROXY -4PREGNENE-3,20-DIONE.
 2. A COMPOUND OF THE FORMULA: